Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is an established genetic risk of hypertension, diabetes, and coronary heart diseases in Asian population. Previous experimental data showed ALDH2 regulated inflammation, a potential mechanism of heart failure with preserved ejection fraction (HFpEF). However, clinically, the association between ALDH2 polymorphism and incidence of HFpEF remains unknown. In this prospective cross-sectional study, ALDH2 genotyping was performed in 613 consecutive patients enrolled with cardiovascular diseases (CVDs), including hypertension, coronary heart diseases, and/or diabetes mellitus, with normal left ventricular ejection fraction (LVEF). HFpEF was diagnosed according to symptoms and/or signs of dyspnea, fatigue or ankle swelling, N-terminal pro-B-Type natriuretic peptide (NT pro-BNP ≥ 280 pg/mL), LVEF ≥ 50%, and at least one additional criterion: left atrial enlargement (left atrial diameter > 40 mm), diastolic dysfunction (E/E' ≥ 13 or E'/A' < 1) or concurrently with atrial fibrillation. Finally, of 613 patients with CVD, 379 patients (61.8%) were assigned to the wild-type ALDH2*1/*1 group and 234 patients (38.2%) to the mutation-type ALDH2*2 group according to genotyping results. Sixty-nine patients (11.3%) were diagnosed with HFpEF. In ALDH2*2 group, the occurrence of HFpEF was higher (15.4% vs. 8.7%, p = 0.011) than that in ALDH2*1/*1 group. Leukocyte count, the indicator of systemic inflammation, was significantly higher (6.9 ± 2.4 × 109/L vs. 6.5 ± 1.9 × 109/L, p = 0.010) in ALDH2*2 group compared to ALDH2*1/*1 group. In conclusion, ALDH2*2 variant is associated with the risk of HFpEF in patients with CVD. Increased systemic inflammation probably involved in this disease process.