Current treatment guidelines for the management of HIV-infected individuals emphasize the importance of excellent adherence to antiretroviral medications. We conducted a prospective 24-week study of adherence to lopinavir/ritonavir in a group of 64 subjects using the Medication Event Monitoring System (MEMS). A range of demographic and clinical information, including cigarette smoking status, was collected from each participant. The overall mean adherence rate of the study cohort was 72.8% (SD = 22.2%). Current smokers took 63.5% (SD = 22.1) of prescribed doses, compared with 84.8% (SD = 15.8%) in nonsmokers (p<.001). We found no difference in adherence rates between ex-smokers and subjects who had never smoked. In a multiple linear regression model, factors independently associated with lower adherence rates included current smoking (p = .001), lower CD4+ lymphocyte count at enrollment (p = .04), and lower educational attainment (p = .04). Depression and history of illicit substance use were not associated with nonadherence. In our study cohort, current cigarette smoking was an important and significant marker of inferior adherence to antiretroviral medication.