We conducted a preliminary RCT among 40 HIV-positive Latinos of Mexican descent on the U.S.-Mexico border who indicated imperfect adherence and depressive symptomatology. Participants were randomly assigned to culturally adapted cognitive-behavioral therapy for adherence and depression with an alarmed pillbox or usual care. Outcomes were depressive symptoms (self-report and blind clinician ratings), adherence (self-report and electronic pillbox), and biological markers. The intervention, delivered in English and Spanish, proved feasible and acceptable. Generalized estimating equations in intent-to-treat analyses showed some effects of "moderate" to "large" size, with maintenance over time. For example, intervention (vs. control) participants demonstrated at post-intervention a greater drop in BDI scores (OR = -3.64, p = 0.05) and greater adherence according to the electronic pillbox (OR = 3.78, p = 0.03). Biological markers indicated some relative improvement for CD4 count but not VL. The promising results suggest a larger trial to determine efficacy is warranted.