Background <p>Internet-based interventions (IBIs) are a low-threshold treatment for individuals with depression. However, comparisons of IBI against unstandardized care-as-usual (CAU) are scarce. Moreover, little evidence is available if IBI has an add-on effect for individuals already receiving an evidence-based treatment such as antidepressants and/or psychotherapy.</p> Method <p>This parallel, two-arm RCT (1:1 allocation ratio, simple randomization) examines the effectiveness of a therapist-guided cognitive-behavioral IBI compared to unstandardized CAU in a self-selected sample of adults (≥ 18&#xa0;years). Eligible individuals reported (a) mild (BDI-II score ≥ 14) to moderately severe (PHQ-9 ≤ 19) symptoms of depression, (b) no acute suicidal ideations, (c) no acute or lifetime (hypo-)mania and/or symptoms of psychosis. We assigned eligible individuals to an intervention (INT) arm or an unstandardized CAU-arm (i.e., we imposed no restrictions on what individuals were allowed to do in the 8-week waiting period). Individuals in the INT-arm got access to a 7-module CBT-based IBI. The primary endpoint is depressive symptom load 9 to 11&#xa0;weeks after randomization. Secondary endpoints included anxiety, self-efficacy, and perceived social support. We report effects for the entire sample (<i>N</i> = 1899), as well as for individuals using the IBI as a stand-alone intervention (<i>n</i> = 1408) or as an add-on to antidepressants (<i>n</i> = 367), psychotherapy (<i>n</i> = 73), or antidepressants and psychotherapy (<i>n</i> = 51). Patients entered the trial with these concurrent treatments (i.e., they were not randomly assigned).</p> Results <p>Concerning all randomized individuals, 62.5% of individuals in the INT-arm accessed all treatment modules within 11&#xa0;weeks. Individuals assigned to the INT-arm reported significantly lower depressive symptoms (PHQ-9: − 2.5, 95% CI [− 2.9, − 2.0], <i>d</i> =  − 0.7; BDI-II: − 5.3, 95% CI [− 6.5, − 4.1], <i>d</i> =  − 0.8) and higher rates of &#xa0;≥ 50% symptom improvements (PHQ-9: 38.5% vs. 14.3%; BDI-II: 44.6% vs. 14.8%) compared to individuals assigned to the CAU-arm. Secondary outcomes also favored INT over CAU, with effect sizes ranging from |<i>d</i>|= 0.18 (social support) to 0.62 (anxiety). Rates of deterioration (PHQ-9: 4.1%; BDI-II: 3.4%) and self-reported side effects (10.5%) were low in the INT-arm. Similar patterns emerged for all strata. However, the between-arm differences failed to reach significance within the strata of individuals using the IBI as an add-on to psychotherapy.</p> Conclusion <p>Our results show that providing interested adults access to the therapist-guided, cognitive-behavioral IBI under investigation is associated with improved mental health outcomes, whether individuals use the IBI as a stand-alone or add-on intervention to another evidence-based treatment. This finding aligns with available studies indicating that IBIs should be considered a low-threshold treatment option for individuals with depression.</p> Trial registration <p>The trial was registered at the Deutsches Studienregister (Trial-Registriation Number/DRKS-ID: DRKS00021106, Date: 25.06.2020).</p>