Infective endocarditis (IE) is one of the most severe complications of parenteral drug abuse. The incidence of IE in intravenous drug abusers (IVDAs) is 2% to 5% per year, being responsible for 5% to 10% of the overall death rate. The prevalence of HIV infection among IVDAs with IE ranges between 30% and 70% in developed countries and HIV-infection by itself increases the risk of IE in IVDAs. The incidence of IE in IVDAs is currently decreasing in some areas, probably due to changes in drug administration habits by addicts to avoid HIV transmission. Overall, Staphylococcus aureus is the most common etiological agent, being usually sensitive to methicillin (MSSA). The tricuspid valve is the most frequently affected (60% to 70%), followed by the mitral and aortic valves (20% to 30%). HIV-positive IVDAs have a higher ratio of right-sided IE and S aureus IE than HIV-negative IVDAs. Response to antibiotic therapy is similar. Drug addicts with non-complicated MSSA right-sided IE can be treated with an i.v. short-course regimen of nafcillin or cloxacillin for 2 weeks, with or without addition of an aminoglycoside during the first 3 to 7 days. The prognosis of right-sided endocarditis is generally good; overall mortality is less than 5%, and with surgery is less than 2%. In contrast, the prognosis of left-sided IE is less favorable; mortality is 20% to 30%, and even with surgery is 15% to 25%. IE caused by GNB or fungi has the worst prognosis. Mortality between HIV-infected or non-HIV-infected IVDAs with IE is similar. However, among HIV-infected IVDAs, mortality is significantly higher in those who are most severely immunosuppressed, with CD4+ cell count < 200/microL or with AIDS criteria. Conversely, IE in HIV-infected patients who are not drug abusers is rare. The epidemiology of cardiac surgery in IVDAs and/or HIV-infected patients has changed in recent years. There is a decrease in IE and an increase of patients undergoing surgery (CABS) for coronary artery disease secondary to the hyperlipidemia and lipodystrophy induced by highly active antiretroviral therapy (HAART). Cardiac surgery in HIV-infected patients with or without IE does not worsen the prognosis because extracorporeal circulation did not affect the immune status after surgery. Morbidity and mortality seems to stay within the same range as the non-infected patients. In our experience, in the IE in HIV-infected IVDA group, the 1-year survival is 65% and the 5 and 10-year actuarial survival is 35%. For patients operated on for coronary artery disease, the 5-year survival is 100%.