A 48-year-old HIV positive man presented with an acute myocardial infarction. The patient had been treated with emtricitabine/tenofovir and fosamprenavir/ritonavir for the past 10 years. Eplerenone 25 mg/day had to be initiated due to a left ventricular dysfunction. One week after discharge, a routine laboratory check-up revealed a severe hyperkalaemia. This adverse effect was suspected to have occurred due to the inhibitory effect of fosamprenavir/ritonavir on CYP3A4 leading to an increase in eplerenone exposure (CYP3A4 substrate) and related hyperkalaemia. The antiretroviral treatment and eplerenone were stopped and serum potassium levels normalized after two weeks.