Introduction: Evidence from developed countries shows the efficacy of computer-assisted cognitive-behavioral therapy (cCBT) in addressing adolescent depression in home and/or school settings. This paper presents the results of a randomized controlled trial (RCT) of a brief therapist-guided cCBT intervention for adolescent depression in resource-constrained primary health care (PHC) settings. Material and methods: A multicenter, two-arm parallel-group, individually RCT with a 1:1 allocation ratio assigned 216 depressed adolescents (aged 15-19) attending four PHC centers in a low-income municipality of Santiago, Chile, to receive eight weekly face-to-face therapist-guided cCBT sessions by study therapists (N = 108), or to receive an enhanced usual care (EUC) intervention by trained PHC psychologists, encouraged to adhere to the national clinical guidelines for the management of depression (N = 108). Both groups received pharmacotherapy concordant with these guidelines. The primary outcome was the Beck Depression Inventory (BDI) at 4 months post-randomization, to assess depressive symptoms. BDI at 6 months post-randomization was a secondary outcome. Additional measures included patients' compliance, and satisfaction with different treatment components, at 6 months post-randomization. Main Results: The adjusted difference in mean BDI score between groups was -3.75 (95% CI -6.23 to -1.28; p = 0.003) at 4 months post-randomization. At 6 months post-randomization, the adjusted difference in mean BDI score between groups was -2.31 (95% CI -4.89 to 0.27; p = 0.078). The effect size was small-to-medium at 4 months post-randomization, d = 0.39 (0.12 to 0.67), and small and non-significant at 6 months post-randomization d = 0.29 (-0.00 to 0.59). Adolescents in the experimental treatment group were significantly more satisfied with treatment, with the PHC centers' facilities, with the psychological care received, and with non-professional staff than those in the comparator treatment group. Discussion: A brief therapist-guided cCBT eight-session intervention improves the response of depressed adolescents attending PHC centers at 4 months post-randomization. At 6 months post-randomization, the differences of between groups were not significant. Future research may focus on exploring strategies to sustain and increase response. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT01862913 and URL: https://clinicaltrials.gov/ct2/show/NCT01862913.