Aims: To study in a randomized placebo-controlled design the efficacy of the antidepressant venlafaxine, a serotonin and a weak noradrenaline reuptake inhibitor, in the treatment of atypical facial pain (AFP). Methods: The study was a randomized, doubleblind, crossover comparison of venlafaxine and a placebo. It consisted of 2 treatment periods, each of 4 weeks’ duration, separated by a 2-week washout period. Thirty patients suffering from chronic pain who had been diagnosed with AFP after a thorough clinical examination were recruited. Pain intensity and pain relief were registered at 6 visits. Anxiety, depression, and adverse effects were recorded. Venous blood samples were collected at the end of each treatment period for the determination of serum levels of venlafaxine and its metabolites. Results: Twenty patients completed the trial. Eight patients discontinued because of adverse effects and 2 patients were excluded because of noncompliance. Two patients completed the trial but were excluded from the analysis because they experienced no pain at the baseline visit. There was no significant difference in pain intensity reduction between the maximum tolerated dose of venlafaxine (75 mg in most cases) and the placebo. Pain relief was significantly greater with venlafaxine than with the placebo treatment. Significantly more escape medication was consumed during the placebo period compared with the venlafaxine period. No significant correlation was found between the serum concentration of the drug and the response to treatment. Anxiety and depression scores did not differ between venlafaxine and placebo treatment. Adverse effects were equally common during both treatments. Conclusion: Venlafaxine was only modestly effective in the treatment of AFP. J OROFAC PAIN 2004;18:131–137