Background. The objective of the study was to determine whether treatment with protease inhibitors is associated with unprotected sexual behavior. Methods. A total of 592 HIV-infected persons recruited from statewide public clinics in nonurban Alabama communities completed an assessment that, among other variables, elicited information on demographics, current sexual practices, health status, and medication use. Associations of treatment with protease inhibitors and high-risk sexual behavior were estimated, adjusting for potential confounders. Results. Treatment with protease inhibitors was not associated with whether a person was sexually active or with high-risk practices among sexually active heterosexual men and women. Among men who had sex with men, however, treatment with protease inhibitors was associated with never using condoms and with inconsistent use of condoms. Conclusions. Clinicians treating patients with protease inhibitors should consider providing risk-reduction counseling.