Rationale: 3,4-Methylenedioxymethamphetamine (MDMA) mainly releases serotonin (5-HT) and is contained in the recreational drug Ecstasy. 5-HT is known to play an important role in mood and anxiety disorders, for which there is a female preponderance. To date, there are no systematic data on gender differences in the subjective effects of MDMA. Objectives: The present work analyzed the pooled data from three controlled studies on the psychological and physiological effects of MDMA in healthy volunteers with no or minimal MDMA experience. A particular focus of the analyses were possible gender differences. Methods: A total of 74 subjects (54 male, 20 female) participated in all three studies. MDMA in oral doses ranging from 70–150 mg (1.35–1.8 mg/kg) was administered under double-blind placebo-controlled conditions. Subjective peak changes were assessed by standardized psychometric rating scales. Physiological measures were blood pressure, heart rate, and peripheral body temperature. Adverse drug effects were assessed during the experimental session and after 24 h. Results: Psychoactive effects of MDMA were more intense in women than in men. Women especially had higher scores for MDMA-induced perceptual changes, thought disturbances, and fear of loss of body control. The dose of MDMA positively correlated with the intensity of perceptual changes in women. Acute adverse effects and sequelae were also more frequent in female than in male subjects. In contrast, men showed higher increases in blood pressure than woman. Conclusions: The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the 5-HT-releasing effects of MDMA. Our results also indicate that increasing doses of MDMA produce more hallucinogen-like perceptual alterations, particularly in women.