Abstract Body (Do not enter title and authors here): Background: Women with heart failure with preserved ejection fraction (HFpEF) exhibit better clinical outcomes than men. In the recent murine model of HFpEF elicited by a high-fat diet (HFD) coupled with N[w]-nitro-l-arginine methyl ester (L-NAME), female mice showed less cardiac remodeling than males, independently from sex hormones. Also, male cardiac macrophages (Mo) from mice are more susceptible to inflammatory stimuli. It is unknown whether cardiac pro-inflammatory Mo derived from monocytes (CCR2⁺MHCII⁺) and resident repair Mo (CCR2^-MHCII⁺ and CCR2^-MHCII^-) differ between males and females. Purpose: To characterize in mice of both genders with HFpEF the cardiac pro-inflammatory and the protective resident repair Mo. Methods: 12-week-old male and female C57BL/6N mice received HFD (60% kcal from fat) and L-NAME (0.65 g/L in drinking water) or control diet during 15 weeks and then sacrified. Cardiac function and cardiac pro-inflammatory and repair Mo were determined. Results: (mean±SEM, n=11-13 mice/group). Compared with males, female mice with HFpEF gained less BW (30% vs 47%, p<0.001) and walked a greater distance on the treadmill (550±52 vs 365±28 mts, p<0.01). Blood pressure was similar and significantly increased in both genders (p< 0.001). Glucose intolerance was observed only in males with HFpEF. The left ventricle septum and posterior wall were thicker in HFpEF males vs controls and HFpEF females (p≤0.001, F=67.1). Left atrium size was increased only in males with HFpEF by 24% (p<0.0001). In the female myocardium, the CCR2^-MHCII^- Mo were significantly increased both in controls and in HFpEF mice vs male (p<0.001, F=11.4). Only in males with HFpEF, the CR2⁺MHCII⁺ Mo increased by 59% (p<0.001, F=12.9) and the CCR2^-MHCII⁺ Mo decreased by 29% (p<0.05, F=3.7). Conclusions: The protective resident Mo (CCR2^-MHCII^-) are significantly increased in the heart of females versus males. In females, the HFpEF did not modify the levels of protective residents Mo which was associated to less CRM and better exercise performance in females versus males. Only in males with HFpEF, the cardiac monocyte-derived macrophages (CCR2⁺MHCII⁺) increased and resident macrophages (CCR2^-MHCII⁺) that are partially replaced by monocytes decreased. The activation of resident cardiac Mo may be an important mechanism for prevention and treatment of cardiac remodeling in HFpEF. FONDECYT 1221585 (MPO), 1231604 (JJ), 1231909 (CAA), 11241074 (PA) and FONDAP 15130011(MPO, LG).