The sympathomimetic agent ephedrine has potent thermogenic and anti-obesity properties in rodents. The effect is markedly enhanced by caffeine, while caffeine given alone has no effect. This study was undertaken to find out if a similar weight reducing synergism between ephedrine and caffeine is present in obese patients. In a randomized, placebo-controlled, double blind study, 180 obese patients were treated by diet (4.2 MJ/day) and either an ephedrine/caffeine combination (20mg/200mg), ephedrine (20 mg), caffeine (200 mg) or placebo three times a day for 24 weeks. Withdrawals were distributed equally in the four groups, and 141 patients completed the trial. Mean weight losses was significantly greater with the combination than with placebo from week 8 to week 24 (ephedrine/caffeine, 16.6 +/- 6.8 kg vs. placebo, 13.2 +/- 6.6 kg (mean +/- s.d.), P = 0.0015). Weight loss in both the ephedrine and the caffeine groups was similar to that of the placebo group. Side effects (tremor, insomnia and dizziness) were transient and after eight weeks of treatment they had reached placebo levels. Systolic and diastolic blood pressure fell similarly in all four groups. We conclude, that in analogy with animal studies, the ephedrine/caffeine combination is effective, while caffeine and ephedrine separately are ineffective for the treatment of human obesity.