IMPORTANCE Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. OBJECTIVE To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. DATA SOURCES We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. STUDY SELECTION Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. DATA EXTRACTION AND SYNTHESIS We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. MAIN OUTCOMES AND MEASURES Patient Health Questionnaire-9 (PHQ-9) scores. RESULTS Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-0 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, -0.8; 95% CI, -1.4 to -0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. CONCLUSIONS AND RELEVANCE In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.