Background: Comorbidities play a major role in heart failure. Whether prevalence and prognostic importance of comorbidities differ between heart failure with preserved ejection fraction (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) is unknown. Methods: Patients from index (n = 2516) and validation cohort (n = 1738) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled. Eight non-cardiac comorbidities were assessed; diabetes mellitus, thyroid dysfunction, obesity, anaemia, chronic kidney disease (CKD, estimated glomerular filtration rate < 60 mL/min/1.73 m2), COPD, stroke and peripheral arterial disease. Patients were classified based on ejection fraction. The association of each comorbidity with quality of life (QoL), all-cause mortality and hospitalisation was evaluated. Results: Patients with complete comorbidity data were included (n = 3499). Most prevalent comorbidity was CKD (50%). All comorbidities showed the highest prevalence in HFpEF, except for stroke. Prevalences of HFmrEF were in between the other entities. COPD was the comorbidity associated with the greatest reduction in QoL. In HFrEF, almost all were associated with a significant reduction in QoL, while in HFpEF only CKD and obesity were associated with a reduction. Most comorbidities in HFrEF were associated with an increased mortality risk, while in HFpEF only CKD, anaemia and COPD were associated with higher mortality risks. Conclusions: The highest prevalence of comorbidities was seen in patients with HFpEF. Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF. Most comorbidities were associated with higher mortality risks, although the associations with diabetes were only present in patients with HFrEF.