Objective: To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF). Methods: A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22). Results: After surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo-derived e′ increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate. Conclusions: Surgery-induced weight loss in women with HFpEF and obesity was associated with improved symptoms, reverse cardiac remodeling, and improved relaxation. Although weight loss was associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. The results of this study suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis.