For a study, it was determined that although there are gender differences in heart failure with preserved ejection fraction (HFpEF), knowledge of the mechanisms behind these variations is limited. The objective of the study was to determine if there are any gender variations in cardiometabolic and exercise hemodynamic characteristics among people with HFpEF. From December 2006 to June 2017, a cross-sectional study was done at a single-center tertiary care referral hospital, with 295 people meeting hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. Using linear and logistic regression models, the researchers looked at sex differences in several components of oxygen transport and use during exercise. From June 2018 until May 2019, the data was evaluated. During cardiopulmonary exercise testing, gas exchange and hemodynamic parameters were measured at rest and during activity. Around 121 (41.0%) of the 295 participants were men (mean [SD] age, 64  years) and 174 (59.0%) were women (mean [SD] age, 61  years). In the tertiary referral group, women with HFpEF had fewer comorbidities, such as diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile, compared to males. Men and women had the same exercise capacity (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P=.38). There was a difference in components of the O2 pathway of men and women, which included worse biventricular systolic reserve (multivariable-adjusted analyses:ΔLVEF β=−1.70; SE, 0.86; P<.05; ΔRVEF β = −2.39, SE=0.80; P=.003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P=.04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P<.001)). Women with HFpEF had larger cardiac and extracardiac impairments, including systolic reserve, diastolic reserve, and peripheral O2 extraction, while having a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity. The gender differences in cardiac and skeletal muscle responses to exercise could shed light on the pathophysiology behind the development of HFpEF and warrant further investigation.