•Heart failure associated comorbidities exert a different effect on all-cause mortality.•Liver cirrhosis (LC) is the comorbidity that most increases the risk of death.•Valvular heart disease (VHD) is the second comorbidity that most increases mortality.•The impact of LC and VHD on prognosis is consistent for the 3 categories of ejection fraction. The role of comorbidities in heart failure (HF) outcome has been previously investigated, although mostly individually. We investigated the individual effect of 13 comorbidities on HF prognosis and looked for differences according to left-ventricular ejection fraction (LVEF), classified as reduced (HFrEF), mildly-reduced (HFmrEF) and preserved (HFpEF). We included patients from the EAHFE and RICA registries and analysed the following comorbidities: hypertension, dyslipidaemia, diabetes mellitus (DM), atrial fibrillation (AF), coronary artery disease (CAD), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), heart valve disease (HVD), cerebrovascular disease (CVD), neoplasia, peripheral artery disease (PAD), dementia and liver cirrhosis (LC). Association of each comorbidity with all-cause mortality was assessed by an adjusted Cox regression analysis that included the 13 comorbidities, age, sex, Barthel index, New York Heart Association functional class and LVEF and expressed as adjusted Hazard Ratios (HR) with 95% confidence intervals (95%CI). We analysed 8,336 patients (82 years-old; 53% women; 66% with HFpEF). Mean follow-up was 1.0 years. Respect to HFrEF, mortality was lower in HFmrEF (HR:0.74;0.64-0.86) and HFpEF (HR:0.75;0.68-0.84). Considering patients all together, eight comorbidities were associated with mortality: LC (HR:1.85;1.42-2.42), HVD (HR:1.63;1.48-1.80), CKD (HR:1.39;1.28-1.52), PAD (HR:1.37;1.21-1.54), neoplasia (HR:1.29;1.15-1.44), DM (HR:1.26;1.15-1.37), dementia (HR:1.17;1.01-1.36) and COPD (HR:1.17;1.06-1.29). Associations were similar in the three LVEF subgroups, with LC, HVD, CKD and DM remaining significant in the three subgroups. HF comorbidities are associated differently with mortality, LC being the most associated with mortality. For some comorbidities, this association can be significantly different according to the LVEF.