OBJECTIVES: This study conducted cost-effective analysis of compliance-enhancing behavioral interventions for highly active antiretroviral therapy (HAART) patients. Behavioral interventions, especially concerning costs and adherence associated with observed therapy and use of medication event monitoring systems (MEMS), are currently poorly covered in the existing literature.METHODS: Cost-effective analysis of Project MOTIV8 (R01MH68197) was conducted on 204 HIV+ patients in Kansas City from 2004 to 2008. The study randomized patients into one of three arms: control, enhanced counseling (EC), and EC plus observed therapy (OT). This study identified and analyzed time, direct and indirect costs associated with conducting randomized clinical trials (RCT) of motivational interviewing-based behavioral interventions to enhance HAART adherence.  Adherence cutoff was set at ≥80% compliance to HAART.  The quality adjusted life values were adapted from previous literature. TreeAge® Pro2009 was used to create decision trees, cost-effectiveness models and sensitivity analysis. ICER and net benefit was calculated based upon a willingness to pay of $50,000/QALY.RESULTS: The direct cost was $125,799($616/patient) and training cost was $9,710($48/patient). The total time cost associated with the recruitment effort came to $245,626($1,204/patient) and evaluation of questionnaires and all patient/professional interactions for all 204 patients was $243,632($1194/patient).  Motivational interviewing costs for 134 EC patients came to $271,133($2023/patient) and $148,570($2321/patient) for 64 OT patients. Total cost per patient: Control=$3062, EC=$5085, EC+OT=$7406.  ICER found that EC and EC/OT were dominated. EC was $38/QALE(month) and EC/OT was $56/QALE(month).  Net benefit analysis showed that 59% of the patients in EC have to be adherent in order to be equivalent. CONCLUSIONS: This study helps to fill in knowledge gaps associated with behavioral interventions on HIV patients, especially concerning costs and adherence associated with observed therapy and use of MEMS.  This economic analysis can serve as a guide for clinicians and policymakers in determining cost-efficient treatment strategies for patients with HIV.