Phenylpropanolamine (PPA), an over-the-counter drug, is used for weight reduction but its effectiveness is controversial. One hundred and one ambulatory subjects (85 female; 16 male), 21-61 years old, 15-45% overweight but otherwise healthy, were studied. The study was divided into two phases: (i) a double blind (DB), placebo-controlled (P) phase in which all subjects took placebo for two weeks and subsequently took PPA, 75 mg sustained release or placebo for six weeks and (ii) an extended double blind phase in which subjects chose to continue up to 20 weeks. All subjects were instructed on a 5023 kJ (1200 kcal) diet. Both groups lost weight at weeks 4, 6 and 8, but the weight loss was greater for the PPA treated (2.59 kg) than for the placebo treated (1.07 kg) subjects (P = 0.01). Dropout was 29.4% for PPA and 44% for placebo treated subjects. In the 36 subjects who chose to continue in the extended double blind study, the difference persisted (PPA 5.1; placebo 0.4 kg) (P = 0.02). No difference between the groups was observed in blood pressure, pulse rate or subjective side effects. In spite of greater weight loss on PPA, patients did not report a greater anorexic effect. We conclude that PPA enhances weight loss in subjects treated with a hypocaloric diet and is free of untoward side effects.