Using CD we show that human group II protamines undergo novel zinc-dependent secondary structure transitions. The CD spectra of protamine is characteristic of random coil proteins with a large minima at 197 nm. Upon the addition of 1 mM zinc, the magnitude of this minima is decreased by 44%. This spectral change is not induced by 1 mM calcium or magnesium. Cadmium, which has chemical properties similar to zinc, can also induce the structural transition although not as effectively as zinc. The spectral changes that accompany zinc binding are indicative of an increase in beta-turn and anti-parallel beta-sheet structures. This is consistent with the predicted secondary structure for protamines which is dominated by beta-turns. Our data support a model in which protamine adopts a folded structure in the presence of zinc. We propose that a zinc-modulated structure is physiologically significant considering the relatively high levels of zinc in human sperm.