Background Repetitive transcranial magnetic stimulation (rTMS) treatment of depression utilizes numerous predetermined patterns of stimulation. As an alternative to using invariant stimulus timing parameters, the interactive technique delivers individual stimuli based on the background electroencephalogram (EEG) activity. Objective This study examines the use of an EEG-dependent technique as a means to enhance the efficacy of rTMS in the treatment of depression. Methods Forty-four patients with treatment-refractory major depression were treated, in a randomized, doubleblind, 4-week trial, with two different rTMS stimulus timing techniques (left dorsolateral prefrontal cortex). Standard rTMS utilized 10-Hz stimuli, whereas interactive rTMS applied individual stimuli in response to a selected pattern of background EEG activity analyzed in real time. Hamilton Depression Rating Scale (HDRS) and the Beck's Depression Inventory-II (BDI) scores were recorded at baseline, 2 weeks and after the final treatment. Results The interactive group showed a trend toward greater efficacy than the standard group in both absolute ( t = −1.68; P = .100) and percentage ( t = −1.74; P = .090) change in scores on HDRS (and similarly BDI). The response rate (>50% reduction) for the interactive technique of 43% (9/21) was also different to that of the standard technique (22%; 5/23; odds ratio: 2.70). Conclusions The use of EEG-based TMS stimuli has been shown to be feasible in an rTMS clinical trial in treatment-resistant depression. The EEG-based interactive technique was associated with an indication of a trend toward a greater clinical effect than the standard rTMS technique. The interactive technique thus has the potential to refine the rTMS methodology and to enhance efficacy in the treatment of depression.