Spermatozoa from oligozoospermic subjects are characterized by a reduced in vitro ability to penetrate hamster oocytes and by a decreased responsiveness to physiological stimuli that trigger the acrosome reaction. One of the first steps in the induction of the acrosome reaction is an increase of intracellular free calcium concentrations ([Ca2+]i). It has been recently shown that progesterone (P) is able to increase [Ca2+]i in capacitated human sperm at concentrations similar to those found in follicular fluid. We evaluated sperm [Ca2+]i increase in response to P (0.1 micrograms/ml) in 19 normo- and 17 oligozoospermic subjects. The average percentage of [Ca2+]i increase over the basal level was significantly lower in spermatozoa from oligozoospermic subjects when compared to normozoospermic subjects (138.7 +/- 8.22% increase in oligo- versus 263.3 +/- 39.7% increase in normozoospermic subjects; P < 0.001). Progesterone-stimulated [Ca2+]i increase was significantly correlated with sperm motility (r = 0.54), sperm concentration (r = 0.96), and sperm morphology (% of normal forms) (r = 0.49). In addition P induced a significant increase of acrosome-reacted spermatozoa in normospermic patients (n = 10), whereas no significant effect was observed in spermatozoa from oligozoospermic men (n = 7). Taken together, these results indicate that spermatozoa from oligozoospermic men have a reduced ability to initiate the cascade of events that lead to the acrosome reaction in response to a physiological stimulus, such as P, and might contribute to explaining the reduced fertilizing capacity of these patients.