Second generation electronic medication adherence monitors provide real-time data on pill bottle opening behavior. Feasibility, validity, and acceptability, however, have not been established. Med-eMonitor is a multi-compartment adherence device with reminder and education capacity that transmits data through a telephone connection. Monthly adherence levels were measured for 52 participants over approximately 3 months using the Med-eMonitor (unadjusted and adjusted for participant confirmed dosing) and unannounced pill counts. HIV RNA was assessed before and after the 3-month period. Acceptability of Med-eMonitor was determined. Over 92% of Med-eMonitor data was transmitted daily. Unannounced pill counts significantly correlated with adjusted Med-eMonitor adherence (r = 0.29, P = 0.04). HIV RNA significantly correlated with unannounced pill counts (r = -0.34, P = 0.02), and trended toward a significant correlation with unadjusted Med-eMonitor adherence (r = -0.26; P = 0.07). Most, but not all, participants liked using the Med-eMonitor. Med-eMonitor allows for real-time adherence monitoring and potentially intervention, which may be critical for prolonging treatment success.