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 20% of hospital admissions and 5% to 10% of the overall death rate. IVDAs often develop recurrent IE. The prevalence of HIV infection among IVDAs with IE ranges between 30% and 70% in urban areas in developed countries. The incidence of IE in IVDAs is currently decreasing in some geographical areas, probably due to changes in drug administration habits undertaken by addicts in order to avoid HIV transmission. Overall, Staphylococcus aureus is the most common etiological agent, being in most geographical areas sensitive to methicillin (MSSA). The remainder of cases is caused by streptocococci, enterococci, GNR, Candida spp, and other less common organisms. Polymicrobial infection occurs in 2% to 5% of cases. The tricuspid valve is the most frequently affected (60% to 70%), followed by the mitral and aortic valves (20% to 30%); pulmonic valve infection is rare (< 1%). More than one valve is infected in 5% to 10% of cases. 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 among HIV-infected or non-HIV-infected IVDAs. Drug addicts with non-complicated MSSA right-sided IE can be treated successfully 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. Surgery in HIV-infected IVDAs with IE does not worsen the prognosis. The prognosis of right-sided endocarditis is generally good; overall mortality is less than 5%, and with surgery 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. Finally, IE in HIV-infected patients who are not drug abusers is rare.