Thrombospondin-2 (TSP-2) is highly expressed in hypertensive heart. Interstitial fibrosis is frequently observed in hypertensive heart, and it is a characteristic feature of heart failure with preserved ejection fraction (HFpEF). We tested here the hypothesis that high TSP-2 serum levels reflect disease severity and can predict poor prognosis of patients with HFpEF. Serum TSP-2 levels were measured by ELISA in 150 patients with HFpEF. HFpEF was defined as left ventricular ejection fraction ≥50 %, B-type natriuretic peptide (BNP) ≥100 pg/ml or E/e′ ≥15. The endpoints were mortality rate, HF-related hospitalization, stroke and non-fatal myocardial infarction. The median serum TSP-2 level was 19.2 (14.4–26.0) ng/ml. Serum TSP-2 levels were associated with the New York Heart Association (NYHA) functional class. Circulating levels of BNP and high-sensitivity troponin T were positively correlated with serum TSP-2 levels. Kaplan–Meier survival curve showed high risk of adverse cardiovascular events in the high TSP-2 group (>median value), and that the combination of high TSP-2 and high BNP (≥100 pg/ml) was associated with the worst event-free survival rate. Multivariate Cox proportional hazard analysis identified TSP-2 as independent predictor of risk of death and cardiovascular events. Circulating TSP-2 correlates with disease severity in patients with HFpEF. TSP-2 is a potentially useful predictor of future adverse cardiovascular events in patients with HFpEF.