This study was conducted to replicate and extend initial positive findings on the usefulness of a Medication Event Monitoring System (MEMS) to assess pill-taking behavior and enhance compliance with bupropion for smoking cessation. Participants (N=55) received MEMS bottles containing bupropion-SR (150 mg) to be taken twice daily for 7 weeks. For participants randomly assigned to the Enhanced Therapy group (n=27), weekly individual smoking cessation therapy sessions included an additional 10 min of MEMS feedback and compliance enhancement counseling using CBT techniques. The Usual Care group (n=28) received weekly individual smoking cessation sessions only. Compliance outcomes included total doses taken and number of doses taken within the prescribed time interval. Results indicated significantly higher compliance over time for the Enhanced Therapy group. Smoking abstinence rates did not differ between the two groups, although results from the pooled sample analysis showed a significant association between level of medication compliance and abstinence status at treatment weeks 3 and 6. Incorporating MEMS-based compliance interventions into smoking pharmacotherapy trials is recommended.