Background Internet-based interventions promise to enhance the accessibility of mental health care for a greater number of people and in more remote places. Their effectiveness has been shown for the prevention and treatment of various mental disorders. However, their potential when delivered as add-on to conventional treatment (ie, blended care) is less clear. Objective The aim of this study is to study the effectiveness of an internet intervention (ASCENSO) implemented in addition to face-to-face treatment as usual (TAU) for depression. Methods A 2-arm, parallel-group, randomized controlled trial was conducted in an outpatient private mental health care center in Chile. In all, 167 adults, diagnosed with major depressive disorder, without severe comorbidities, and with internet access, were included. Eighty-four participants were assigned to the intervention group and received medical and psychological TAU from the mental health center plus access to the ASCENSO online platform. The control group (n=83) received only TAU. The ASCENSO platform includes psycho-educational information, depressive symptom monitoring and feedback, and managing emergencies based on the principles of cognitive behavioral therapy. Emergency management was mental health provider–assisted. TAU includes access to primary care physicians and psychiatrists, to a brief individual psychotherapy, and to medication when needed. The baseline questionnaires were administered in person, and 6- and 9-months assessments were conducted online. Depression symptoms and quality of life were measured by self-administered questionnaires, and treatment adherence was determined via the Mental Health Center’s internal records. The usage of ASCENSO was assessed by server logs. Reduction on depressive symptomatology was considered as the primary outcome of the intervention and quality of life as a secondary outcome. Results Of the 84 participants in the intervention group, 5 participants (6%) never accessed the online platform. Of the remaining 79 participants who accessed ASCENSO, 1 (1%, 1/79) did not answer any of the symptom questionnaire, and most participants (72/79, 91%) answered the monitoring questionnaires irregularly. The ASCENSO intervention implemented in addition to face-to-face care did not improve the outcome of the usual care delivered at the mental health center, either in terms of reduction of depressive symptoms (F2,6087= 0.48; P=.62) or in the improvement of quality of life (EQ-5D-3L: F2,7678=0.24; P=.79 and EQ-VAS: F2,6670= 0.13; P=.88). In contrast, for the primary (F2,850=78.25; P<.001) and secondary outcomes (EQ-5D-3L: F2,1067=37.87; EQ-VAS: F2,4390= 51.69; P<.001) in both groups, there was an improvement from baseline to 6 months (P<.001), but there was no change at 9 months. In addition, no effects on adherence to or use of TAU were found. Finally, the dropout rate for the face-to-face treatment component was 54% (45/84) for the intervention group versus 39% (32/83) for the control group (P=.07). Conclusions The fact that the adjunctive access to ASCENSO did not improve outcome could be due to both the rather high effectiveness of TAU and to patients’ limited use of the online platform. Trial Registration ClinicalTrials.gov NCT03093467; https://clinicaltrials.gov/ct2/show/NCT03093467