Self-guided internet-based cognitive behavioral therapy (iCBT) has the potential to increase access and availability of evidence-based therapy and reduce the cost of depression treatment.To estimate the effect of self-guided iCBT in treating adults with depressive symptoms compared with controls and evaluate the moderating effects of treatment outcome and response.A total of 13?384 abstracts were retrieved through a systematic literature search in PubMed, Embase, PsycINFO, and Cochrane Library from database inception to January 1, 2016.Randomized clinical trials in which self-guided iCBT was compared with a control (usual care, waiting list, or attention control) in individuals with symptoms of depression.Primary authors provided individual participant data from 3876 participants from 13 of 16 eligible studies. Missing data were handled using multiple imputations. Mixed-effects models with participants nested within studies were used to examine treatment outcomes and moderators.Outcomes included the Beck Depression Inventory, Center for Epidemiological Studies-Depression Scale, and 9-item Patient Health Questionnaire scores. Scales were standardized across the pool of the included studies.Of the 3876 study participants, the mean (SD) age was 42.0 (11.7) years, 2531 (66.0%) of 3832 were female, 1368 (53.1%) of 2574 completed secondary education, and 2262 (71.9%) of 3146 were employed. Self-guided iCBT was significantly more effective than controls on depressive symptoms severity (?=?-0.21; Hedges g ?=?0.27) and treatment response (?=?0.53; odds ratio, 1.95; 95% CI, 1.52-2.50; number needed to treat, 8). Adherence to treatment was associated with lower depressive symptoms (?=?-0.19; P?=?.001) and greater response to treatment (?=?0.90; P?