Objective: Computerized cognitive-bias modification (CBM) protocols are rapidly evolving in experimental medicine yet might best be combined with Internet-based cognitive behavioral therapy (iCBT). No research to date has evaluated the combined approach in depression. The current randomized controlled trial aimed to evaluate both the independent effects of a CBM protocol targeting imagery and interpretation bias (CBM-I) and the combined effects of CBM-I followed by iCBT. Method: Patients diagnosed with a major depressive episode were randomized to an 11-week intervention (1 week/CBM-I +10 weeks/iCBT; n = 38) that was delivered via the Internet with no face-to-face patient contact or to a wait-list control (WLC; n = 31). Results: Intent-to-treat marginal models using restricted maximum likelihood estimation demonstrated significant reductions in primary measures of depressive symptoms and distress corresponding to medium-large effect sizes (Cohen’s d = 0.62–2.40) following CBM-I and the combined (CBM-I + iCBT) intervention. Analyses demonstrated that the change in interpretation bias at least partially mediated the reduction in depression symptoms following CBM-I. Treatment superiority over the WLC was also evident on all outcome measures at both time points (Hedges gs = .59 –.98). Significant reductions were also observed following the combined intervention on secondary measures associated with depression: disability, anxiety, and repetitive negative thinking (Cohen’s d = 1.51–2.23). Twenty-seven percent of patients evidenced clinically significant change following CBM-I, and this proportion increased to 65% following the combined intervention. Conclusions: The current study provides encouraging results of the integration of Internet-based technologies into an efficacious and acceptable form of treatment delivery.