Based on previous experience with parenteral prostanoids, we studied the effect of misoprostol treatment, an orally administered prostaglandin E1 analog, in patients with erythromelalgia. Treatment with placebo was followed by treatment with misoprostol (0.4-0.8 mg per d), both for 6 wk. The patients (n=21) and a study nurse who administered the trial were blinded. The endpoints were change in pain and need for cooling and global assessment of the treatment. Following central body heat provocation, global skin perfusion, capillary morphology, and change in pain were also recorded before and after each treatment period. Results were compared with data from healthy control subjects (n=11) that did not undergo treatment. Clinical safety and tolerability evaluation included physical examinations, clinical laboratory tests, and monitoring of adverse events. All clinical outcome measures were significantly better after treatment with misoprostol (p<0.01) as compared with placebo treatment and after a 3- mo follow-up without treatment. The heat-induced increase in global perfusion after misoprostol treatment was similar to the control group and significantly lower when compared with baseline (p<0.01) and placebo treatment (p<0.05), respectively. This study demonstrates that misoprostol is clinically superior to placebo in patients with erythromelalgia. The results of the perfusion studies may imply that the mechanism of action of the beneficial effect of misoprostol is reduced microvascular arteriovenous shunting in affected skin.