Background: The majority of studies investigating the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a treatment for major depression have focused on high-frequency rTMS to the left prefrontal cortex (HFL-rTMS). In addition, low-frequency right prefrontal rTMS (LFR-rTMS) has also been shown to have antidepressant properties. To date only a small number of studies have directly compared the efficacy of these two approaches. Methods: The aim of this study, therefore, was to investigate further whether LFR-rTMS is as effective as HFL-rTMS in the treatment of major depression. Twenty-seven patients were randomized to one of two treatment arms (HFL-rTMS or LFR-rTMS) for 3 weeks with a possible 1-week extension. Non-responders were offered the opportunity of crossing over to the other treatment type. Stimulation parameters for HFL-rTMS were 30 stimulation trains of 5 s duration at 100% of the resting motor threshold (RMT); for LFR-rTMS, stimulation was applied in four trains of 180 s duration (30 s inter-train interval) at 110% of the RMT. Stimulation was provided 5-week days per week. Results: There were significant improvements seen from baseline to end point irrespective of group and on all clinical outcome measures. In addition, there was no deterioration in any of the measures used to assess cognitive change, and significant improvements were seen on measures of immediate verbal memory and verbal fluency. Conclusions: HFL-rTMS and LFR-rTMS appear to be equally efficacious in treating major depression. This study adds to the growing literature supporting LFR-rTMS as an additional viable method of rTMS delivery in the treatment of depression. Depression and Anxiety, 2009. © 2008 Wiley-Liss, Inc.