Background Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. However, gender differences in intestinal stem cell physiology have been poorly studied. Given the important role of the protease-activated receptor PAR.sub.2 in the control of colon epithelial primitive cells and cell cycle genes, we have performed a sex-based comparison of its expression and of the effects of PAR.sub.2 activation or knockout on cell proliferation and survival functions. Methods Epithelial primitive cells isolated from colons from male and female mice were cultured as colonoids, and their number and size were measured. PAR.sub.2 activation was triggered by the addition of SLIGRL agonist peptide in the culture medium. PAR.sub.2-deficient mice were used to study the impact of PAR.sub.2 expression on colon epithelial cell culture and gene expression. Results Colonoids from female mice were more abundant and larger compared to males, and these differences were further increased after PAR.sub.2 activation by specific PAR.sub.2 agonist peptide. The proliferation of male epithelial cells was lower compared to females but was specifically increased in PAR.sub.2 knockout male cells. PAR.sub.2 expression was higher in male colon cells compared to females and controlled the gene expression and activation of key negative signals of the primitive cell proliferation. This PAR.sub.2-dependent brake on the proliferation of male colon primitive cells was correlated with stress resistance. Conclusions Altogether, these data demonstrate that there is a sexual dimorphism in the PAR.sub.2-dependent regulation of primitive cells of the colon crypt. Keywords: Colon primitive cells, Sexual dimorphism, Protease-activated receptor