Adverse drug reactions occur at a greater frequency in HIV-infected individuals. A 38-year-old Eritrean man was treated with outpatient co-trimoxazole for confirmed Pneumocystis jirovecii pneumonia, but was switched to clindamycin and primaquine due to nausea and vomiting. Following development of methaemaglobinaemia, he was recommenced on prophylactic co-trimoxazole. He was later found moribund with features resembling septic shock and required invasive respiratory support. The diagnosis of a rare, but severe reaction to co-trimoxazole did not become apparent until he was rechallenged with prophylactic co-trimoxazole after recovery from his initial severe reaction. In an era of polypharmacy and an increasing availability of novel drugs, this case is a timely reminder to clinicians of the ongoing need for pharmacovigilance, especially in HIV-infected individuals who may have unusual presentations of an adverse drug reaction.