There is abundant evidence for abnormalities of both norepinephrine and serotonin neurotransmitter systems in post-traumatic stress disorder (PTSD). Venlafaxine extended-release formulation (venlafaxine XR) is a serotonin and norepinephrine re-uptake inhibitor with antidepressant and anxiolytic properties relevant to the pathophysiology of PTSD. Venlafaxine XR is currently approved for the treatment of panic disorder, generalized anxiety disorder and social anxiety disorder, as well as major depression in adults, based on a number of randomized, double blind, placebo-controlled clinical trials. Limited data also demonstrate that venlafaxine XR maintains a therapeutic response for more than 6 months in these anxiety disorders. Venlafaxine XR has demonstrated short- and long-term efficacy for the treatment of PTSD in two recent randomized, double-blind, placebo-controlled clinical trials, although it has not been extensively studied for PTSD, compared with other anxiety disorders. This review focuses on the potential role of venlafaxine XR in the treatment of PTSD, based on currently available evidence.