A 68-year-old Caucasian man (73 kg) was treated for an early postoperative hip prosthesis infection with Staphylococcus epidermidis in October 2017. His past medical history included type 2 diabetes, peripheral artery disease, previous coronary artery bypass surgery, a stroke and two episodes of pulmonary tuberculosis, treated in 1994 and 2008. After surgical debridement of the prosthesis the patient was started on antibiotic therapy with daptomycin. Rifampicin 450 mg twice daily per os (p.o.) was added 12 days postoperatively when the wound was dry, according to treatment concepts of prosthetic joint infections []. However, the wound began to discharge again and C-reactive protein (CRP) rose from 90 mg/l to 439 mg/l, and rifampicin was stopped after 3 days of treatment. Common sources of hospital-acquired infections were excluded. Ultrasound examination and joint aspiration did not indicate the presence of an uncontrolled infection. Rifampicin was therefore recommenced a week later. Two hours after the first rifampicin dose, the patient presented with dyspnea which proved to be rapidly progressive. On clinical examination the patient was hypertensive with a normal heart rate, subfebrile (temperature 37.5 °C), tachypnoeic with an oxygen saturation of 78% on room air, and showed ubiquitous pulmonary crackles. He furthermore developed anuria. A computed tomography (CT) scan of the chest showed ubiquitous ground-glass pattern infiltrations. Rifampicin and daptomycin were stopped. The patient was started on hemofiltration for anuric renal failure with marked metabolic acidosis (base excess 18.2, bicarbonate 8.4 mmol/l). His respiratory failure was managed with supplemental oxygen. Laboratory results during the next few days indicated severe acute liver injury as manifest by massively elevated liver function tests with peak values 2 days after re-exposure to rifampicin (AST 11′115 U/l or 330 times upper limit of normal (ULN), ALT 1′803 U/l or 30 times ULN, LDH 11′883 U/l, total bilirubin 98 μmol/l, spontaneous INR 2.4; previous values all within normal range). Further laboratory abnormalities were eosinophilia (maximum 0.91 G/l), a fall in hemoglobin from 100 g/l to 60 g/l, a positive direct Coombs test, a moderate number of fragmentocytes on the blood film, a urinary sediment with non- glomerular microhematuria without casts, and nephrotic-range proteinuria. The haptoglobin concentration was within the normal range. Follow-up CT scan of the chest on day 7 after exposure showed progressive ground-glass infiltrations in a “crazy paving” pattern and changes of early fibrosis with new traction bronchiectasis, consistent with hypersensitivity pneumonitis. A broncho-alveolar lavage performed on the same day yielded a negative culture, and a cytology specimen showing a moderate cellular infiltration (full cell count 169/ul; ULN 300/ul) of predominantly macrophages (53%) and neutrophil granulocytes (37%). Eosinophilic pneumonia triggered by daptomycin could therefore be excluded. The patient was started on intravenous steroids (initially methylprednisolone 125 mg once daily (od)) due to the progressive pulmonary changes and daptomycin was re-introduced. Transaminases returned to normal within 1 week. Apart from the temporarily elevated INR, there was no evidence of impaired liver synthetic function. Renal function recovered sufficiently so that hemofiltration could be stopped after 2 weeks, but serum creatinine took 2 months to return to normal range. Pulmonary oxygenation also improved significantly after 2 weeks and a follow up chest CT scan 2 months later no longer showed ground glass infiltrations. Prednisolone was tapered over 2 months as allowed by the clinical course (methylprednisolone 125 mg od for 4 days followed by oral prednisolone 60 mg od for 2 weeks, 40 mg od for 3 weeks, 20 mg od for 3 weeks). A review of the patient’s tuberculosis treatment records from 9 years previously revealed that management was modified at that time to a rifampicin-free regimen within 8 days of starting treatment due to a suspected rifampicin-hypersensitivity reaction that included kidney failure and hemolytic anemia. A multi-organ hypersensitivity reaction in a patient previously sensitized to rifampicin was therefore diagnosed. Biopsy-confirmation was not performed on account of the suggestive clinical picture, coagulopathy and limited sensitivity after the introduction of steroids. A Rifampicin-specific lymphocyte transformation test (LTT; performed by ADR-AC GmbH, Berne, Switzerland) 3 weeks after exposure was positive even under steroid treatment. In summary, our patient showed severe acute kidney failure, hypersensitivity pneumonia, acute liver injury and moderate haemolytic anemia after re-exposure to rifampicin.