We analyzed the relationship between viral drug resistance and causes of death in 29 HIV-1–infected patients who had been followed in an HIV-outpatient clinic and died in 1999. Six patients (21%) died with plasma HIV-RNA levels <1000 copies/ml. Seven (24%) died with wild-type (WT) virus in plasma, 6 (21%) had reverse transcriptase (RT) mutations only, 10 (34%) had multidrug-resistant (MDR) virus. The causes of death were not differently distributed among these groups; however, 8 of 16 patients (50%) with resistant viruses died of end-organ failure versus 2 of 7 patients (29%) with WT virus. Seventeen of 32 patients (53%) were thought by their physicians to be noncompliant with prescribed therapy. Major resistance mutations to antiretroviral drugs were present in viruses from at least 55% of our HIV-1–infected patients who died in 1999. Nonetheless, deaths also occurred among patients with well-controlled HIV infection and among patients with WT virus in plasma. Infections related to incomplete immune restoration, inability to maintain suppressive antiretroviral drug levels, and end-organ failures all contribute to mortalities in the era of highly active antiretroviral therapy.