In order to elucidate the effects of ionized calcium and calcium channel blockers on human sperm motility, an in vitro study was conducted looking at the effects of exogenous calcium, ethylene diamine tetraacetic acid (EDTA), diltiazem and dibutyrl cyclic adenosine monophosphate (db-cAMP) on per cent motility and mean velocity of human sperm. Washed spermatozoa from 21 fertile donors were incubated with ionized calcium (zero, five, 10 and 50 mM), EDTA (one and 10 mM), diltiazem (one, 10, 100 microM and one mM) and cAMP (five mM). Per cent motility and mean velocity determinations were made at 10 and 120 min. by computerized analysis of videomicrographs. Over a wide range of extracellular ionized calcium concentrations (50 microM to 50 mM), per cent motility and mean velocity of human sperm were not stimulated or inhibited. At ionized calcium concentration less than 1 microM, achieved by addition of EDTA (10 mM), per cent motility decreased by 68% and 79% and mean velocity decreased by 44% and 48% compared to controls at 10 and 120 min. respectively (p less than 0.001). The decrease in mean velocity was reversible by addition of calcium to the EDTA (10 mM) sample to return ionized calcium to control concentration (0.5 mM). This reversibility suggests EDTA did not have a direct toxic effect on spermatozoa and that its action was mediated by changes in ionized calcium concentration. Diltiazem (one mM) decreased sperm mean velocity by 26% and 28% compared to controls at 10 and 120 min. respectively (p less than 0.01), but had no effect at lower concentrations (one, 10 or 100 microM). Db-cAMP (five mM) increased per cent motility by 25% and 20% and mean velocity by 36% and 34% compared to controls at 10 and 120 min. respectively (p less than 0.05). These results indicate that a minimum level of extracellular ionized calcium is essential to normal sperm motility and suggest that sperm are more dependent on the intracellular translocation of calcium ions for the regulation of motility than on the extracellular ionized calcium concentration. While db-cAMP does significantly increase per cent motility and mean velocity of human sperm, its clinical usefulness for the treatment of male infertility remains to be demonstrated.