OBJECTIVE To test the effect of SR 49059, an orally active, nonpeptide, selective and specific antagonist of the vasopressin V1a receptors in humans. METHODS A placebo-controlled, double-blind, cross-over trial. METHODS The Department of Obstetrics and Gynaecology, Lund University Hospital, Sweden. METHODS Twelve healthy women, who had previously been sterilised by tubal ligation. METHODS The women participated on days 1, 2 or 3 of two menstrual cycles, with intrauterine pressure recordings and intravenous bolus injections of 10 pmol/kg body weight of lysine vasopressin given 1 h before and at 1, 2 and 3 h after oral administration of 300 mg of the study drug or of placebo. METHODS The area between the recording curve and zero level of pressure. Vital signs, safety parameters and drug plasma concentrations were also measured. RESULTS The spontaneous uterine activity as well as the response to lysine vasopressin injections before administration of the test drugs were almost identical at the two experiments. Following intake of SR 49059 the area under the recording curve (0-10 min) after the second, third, and fourth injection of lysine vasopressin were reduced by 57, 42, and 66%, respectively, compared with placebo. Trough plasma concentrations of lysine vasopressin were markedly higher and systolic blood pressure slightly lower after antagonist administration than after placebo, whereas no significant difference between treatments was observed in diastolic pressure, heart rate or plasma osmolality. CONCLUSIONS This study demonstrates for the first time a biological effect of an orally active vasopressin V1a antagonist in humans in vivo and the results support the importance of vasopressin in uterine activation. The differences between study drug and placebo treatments in lysine vasopressin levels and systolic blood pressure, but lack of difference in osmolality indicate that SR 49059 antagonises the effect of lysine vasopressin on the vasopressin V1a receptor, but not that on the vasopressin V2 one. It is suggested that SR 49059 be explored therapeutically in dysmenorrhoea.