This study identifies factors associated with high-risk sexual and drug injection behaviors among human immunodeficiency virus (HIV)-infected injection drug users (IDUs) after initiation of highly active antiretroviral therapy (HAART). Participants of a large cohort study of IDUs in Baltimore were seen at semiannual visits; blood samples to determine HIV serostatus and CD4+ cell count were obtained, as well as questionnaire data on risk behaviors and medication. Survival analysis conducted for 190 HIV-infected participants who initiated HAART during 1996-2000 revealed that an increase in CD4+ cell count (categorized as an increase of >0 cells/mm3 or of < or =0 cells/mm3) after HAART initiation was independently associated with engaging in any sexual intercourse (adjusted relative hazard [ARH], 1.83; 95% CI, 1.22-2.73) and with a 3-fold increase in the hazard of engaging in unprotected sexual intercourse (ARH, 3.29; 95% CI, 1.57-6.93) after HAART initiation. An increase in CD4+ cell count after HAART initiation was not associated with injection of drugs or needle sharing. Risk reduction counseling remains important, despite improvements in the treatment of HIV infection.