The effect of intravenous and intrauterine administration of PGE1 or PGE2 and PGF2 alpha as well as oral administration of PGE2 on the sensitivity and reactivity of the nonpregnant human uterus was studied. With the use of the flaccid microballoon technique or a micro transducer catheter, uterine recordings were made at frequent intervals throughout the menstrual cycle. Independently of the route of administration and of the phase of the cycle, treatment with PGF2 alpha invariably resulted in stimulation of uterine motility. A high sensitivity to PGF2 alpha was noted during the late secretory phase both in normal and dysmenorrheic women. A marked decrease in sensitivity to both PGE2 and PGF2 alpha administered by the intrauterine route was observed in the periovulatory phase. Inhibition of uterine contractility by PGE2 following both intrauterine and oral administration was noted during active menstrual bleeding in normal as well as in dysmenorrheic women. These findings suggest that endogenous prostaglandins may play a role in the regulation of the normal uterine motility during the menstrual cycle and that the main reason for the abnormal contractility pattern seen in dysmenorrheic women during menstrual bleeding is an increased PGF2 alpha/PGE2 ratio.