Abstract Background Adherence to antiretroviral medication regimens is essential to good clinical outcomes for HIV-infected patients. Little is known about the costs of case management (CM) designed to improve adherence for patients identified as being at risk for poor adherence in resource-constrained settings. This study analyzed the costs, outputs, unit costs and correlates of unit cost variation for CM services in 14 ART sites in Ethiopia from October 2008 through September 2009. Methods This study applied standard micro-costing methods to identify the incremental costs of the CM program. We divided total CM-attributable costs by three output measures (patient-quarters of CM services delivered, number of patients served and successful patient exits) to derive three separate indices of unit costs. The relationships between unit costs and two operational factors (scale and service-volume to staff ratios) were quantified through bivariate analyses. Results The CM program delivered 4,598 patient-quarters of services, serving 5,056 patients and 1,995 successful exits at a cost of $167,457 over 12 months, or $36 per patient-quarter, $33 per patient served and $84 per successful exit from the CM program. Among the 14 sites, mean costs were $11,961 (sd, $3,965) for the 12-month study period, and $51 (sd, $36) per patient-quarter; $48 (sd, $32) per patient served; and $183 (sd, $157) per successful exit. Unit costs varied inversely with scale (r, -0.70 for cost per patient-quarter versus patient-quarters of service) and with the service-volume to staff ratio (r, -0.68 for cost per patient-quarter versus staff per patient-quarter). Conclusions For those receiving CM, the program adds 0.52% to the lifetime cost of ART. These data reflect wide variation in unit costs among the study sites and suggest that high patient volume may be a major determinant of CM program efficiency. The observed variations in unit costs also indicate that there may be opportunities to identify staffing patterns that increase overall program efficiency.