Impaired social interaction is a defining feature of autism spectrum disorder, a neurodevelopmental disorder that shows a strong male preponderance in prevalence. Studies have identified neural circuits, neuromodulators and genetic factors involved in social behaviors, but mechanistic understanding of gender-specific social deficits is lacking. We report that deletion of the caspase-3 gene, encoding a protease with functions in apoptosis and neural plasticity, alters specific social behaviors in male mice, while leaving females unaffected. Casp3(-/-) mice showed normal behavioral responses to olfactory cues from food, neutral chemical and biological sources. Both Casp3(-/-) males and females displayed robust social exploration, sociability, recognition and preference for an enclosed novel mouse in the three-chamber test. However, Casp3(-/-) males showed significantly reduced social interaction behaviors when exposed to a freely moving novel mouse, including decreased interaction time and diminished mounting. Thus caspase-3 is essential for a subset of social behaviors, but despite similar hyper-locomotion in both sexes, only male Casp3(-/-) mice exhibited social interaction deficits, which is interesting given the male bias of autism.