The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery-Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.Neuropsychopharmacology advance online publication, 14 January 2009; doi:10.1038/npp.2008.233.