Background Digital health apps are efficacious treatment options for mild-to-moderate depressive disorders. However, the extent to which psychological guidance increases the efficacy of these apps is controversial. Objective We evaluated the efficacy of a web-based intervention, called Selfapy, for unipolar depression. We also investigated differences between psychotherapist-guided and unguided versions. Methods Selfapy is a cognitive behavioral therapy–based intervention for depressive disorders. Participants with mild-to-severe depressive disorders were assigned randomly to participate in either guided (weekly 25-minute duration telephone calls) intervention, unguided version, or waiting list (control group) for 12 weeks. We assessed depressive symptoms at the start of the study, midway through the intervention (6 weeks), at the end of the intervention (12 weeks), and at follow-up (6 months). The main outcome was difference in the Beck Depression Inventory score between the start of the study and the end of the intervention. Secondary outcomes were the Quick Inventory of Depressive Symptomatology—Self Report, the Hamilton Rating Depression Scale, and the Beck Anxiety Inventory. Results Of 401 participants, 301 participants (75.1%) completed the intervention. Changes in the Beck Depression Inventory from baseline differed significantly between groups at the postintervention (F2,398=37.20, P<.001). The reductions in scores for both guided and unguided intervention groups were greater than that for the control group, with large between-group effect sizes (guided vs control: d=1.63, 95% CI 1.37 to 1.93; unguided vs control: d=1.47, 95% CI 1.22 to 1.73) at postintervention. No significant differences were found between guided and unguided intervention groups (P=.18). At follow-up (6 months), treatment effects on the primary outcome were maintained for both intervention groups (guided: F1,194=0.62, P>.999; unguided: F1,176=0.13, P>.999). Conclusions Both guided and unguided versions of the intervention were highly effective in reducing depressive symptoms. Follow-up data suggest that these effects could be maintained. The guided version was not superior to the unguided version. Trial Registration German Clinical Trials Register DRKS00017191; https://tinyurl.com/2p9h5hnx International Registered Report Identifier (IRRID) RR2-10.1186/s13063-021-05218-4