Objective To evaluate the feasibility of a comprehensive, interdisciplinary adherence program aimed at HIV patients. Setting Two centers of the Swiss HIV Cohort Study: Lausanne and Basel. Method 6-month, pilot, quasi-experimental, 2-arm design (control and intervention). Patients starting a first or second combined antiretroviral therapy line were invited to participate in the study. Patients entering the intervention arm were proposed a multifactorial intervention along with an electronic drug monitor. It consisted of a maximum of six 30-min sessions with the interventionist coinciding with routine HIV check-up. The sessions relied on individualized semi-structured motivational interviews. Patients in the control arm used directly blinded EDM and did not participate in motivational interviews. Main outcome measures Rate of patients' acceptance to take part in the HIV-adherence program and rate of patients' retention in this program assessed in both intervention and control groups. Persistence, execution and adherence. Results The study was feasible in one center but not in the other one. Hence, the control group previously planned in Basel was recruited in Lausanne. Inclusion rate was 84% (n = 21) in the intervention versus 52% (n = 11) in the control group (P = 0.027). Retention rate was 91% in the intervention versus 82% in the control group (P = ns). Regarding adherence, execution was high in both groups (97 vs. 95%). Interestingly, the statistical model showed that adherence decreased more quickly in the control versus the intervention group (interaction group × time P < 0.0001). Conclusion The encountered difficulties rely on the implementation, i.e., on the program and the health care system levels rather than on the patient level. Implementation needs to be evaluated further; to be feasible a new adherence program needs to fit into the daily routine of the centre and has to be supported by all trained healthcare providers. However, this study shows that patients' adherence behavior evolved differently in both groups; it decreased more quickly over time in the control than in the intervention group. RCTs are eventually needed to assess the clinical impact of such an adherence program and to verify whether skilled pharmacists can ensure continuity of care for HIV outpatients.