Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia/reperfusion (I/R) damage has not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the Hypertrophic Heart Rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R (compared to control Normal Heart Rat, NHR) were investigated ex vivo. Ventricular weight index was markedly increased in HHR female (7.82 ± 0.49 vs 4.80 ± 0.10 mg/g, P<0.05) and male (5.76 ± 0.22 vs 4.62 ± 0.07 mg/g, p<0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males (dP/dtmax mmHg/s; NHR: 4036 ± 171 vs 4258 ± 152; HHR: 3974 ± 160 vs 4540 ± 259; p<0.05). HHR hearts were more susceptible to I/R (I= 25min, R= 30min) injury than NHR hearts (decreased functional recovery, increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/dt_max) post I/R relative to male NHR (95.0 ± 12.2 vs 60.5 ± 9.4%), a resistance to post-ischemic dysfunction not evident in female HHR (29.0 ± 5.6 vs 25.9 ± 6.3 %). Ventricular fibrillation was suppressed and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus, the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to ischemia-reperfusion insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.