Abstract Introduction Heart failure (HF) affects platelet activation, function, as well as the production of platelets from megakaryocytes. Low platelet counts have been described in HF patients, however without clear distinction whether this is a consequence of HF severity or an independent comorbidity contributing to worse outcomes. Aim Our purpose was to assess the prognostic role of thrombocytopenia in HF patients. Methods Patients with HF admitted to our Cardiology Department were included in this study, after excluding acute coronary syndromes, pulmonary embolisms, infections, malignancy and hepatic cirrhosis. Thrombocytopenia was defined as a platelet number below 15ehz747.0353/uL and classified as severe below 5ehz747.0353/uL and moderate between 5ehz747.0353–1ehz747.03530/uL. Patients with a left ventricular ejection fraction (LVEF) <40% were classified as HF with reduced EF (HFrEF), those with a LVEF between 40 and 49% as HF with mid-range EF (HFmrEF) and the rest as HF with preserved EF (HFpEF). All-cause mortality was assessed after a mean follow-up of 5.5 years. Results We included 1142 patients, with a mean age of 72.45±10.53 and 51.6% female. 121 (10.6%) patients had thrombocytopenia, of which 3 had severe thrombocytopenia and 21 had moderate thrombocytopenia. All-cause long-term mortality was 43.8%. Patients with acute decompensated heart failure had similar prevalence of thrombocytopenia as those with stable heart failure (12.3% vs 9.5%, p=0.22). Patients with thrombocytopenia had a higher risk ratio for all-cause mortality compared to patients with normal platelet counts (RR 1.35, 95% CI 1.14–1.60, p=0.002). Patients with severe thrombocytopenia had a risk ratio of 2.29 (95% CI 2.14–2.45, p=0.049), those with moderate thrombocytopenia had a risk ratio of 1.80 (95% CI 1.39–2.33, p=0.006) and those with mild thrombocytopenia had a risk ratio of 1.23 (95% CI 1.01–1.51, p=0.06) of all-cause long-term mortality, compared to patients with normal platelet counts. Patients with thrombocytopenia and HFpEF (RR 1.66, 95% CI 1.16–2.37, p=0.021) or HFrEF (RR 1.35, 95% CI 1.09–1.68, p=0.03) had higher risk of all-cause long-term mortality, but not those with HFmrEF and thrombocytopenia (RR 1.09, 95% CI 0.67–1.76, p=0.73), possibly due to the predominance of mild thrombocytopenia (80.9%). In multiple regression analysis, after adjusting for age and sex, alongside NT-proBNP levels and left ventricular ejection fraction, moderate thrombocytopenia (p=0.031) was an independent predictor of all-cause long-term mortality, but not mild thrombocytopenia (p=0.415). Due to the very low number of patients, no multiple regression analysis could be computed with severe thrombocytopenia. Conclusions Thrombocytopenia is an independent predictor of mortality in HF patients, especially platelet counts below 1ehz747.03530/uL. In both patients with HFrEF and HFpEF this biomarker should be assessed for prognosis.