In the present study, we demonstrated that both male and female Ldlr−/−Diaph1−/− mice displayed significantly less atherosclerosis at the aortic sinus compared with Ldlr−/− mice; however, in both sexes, although the mice devoid of both Ldlr−/− and Diaph1−/− displayed significantly lower plasma concentrations of cholesterol compared to that observed in Ldlr−/− mice; only in male but not female Ldlr−/−Diaph1−/− mice, were significant reductions in plasma concentrations of triglyceride also observed. Here, DIAPH1 is linked to atherosclerosis.