Background During COVID‐19 outbreak, Italy was the first country in Europe to be heavily affected with an intensive care unit mortality of 26%. In order to reduce this percentage, physicians should establish clear and objective criteria to stratify COVID‐19 patients at high risk of in‐hospital death. Thus, the aim has been to test a large spectrum of variables ranging from clinical evaluation to laboratory biomarkers to identify which parameter would best predict all‐cause in‐hospital mortality in COVID‐19 patients. Design observational study. Results Multivariate Cox regression analysis showed that each 5 years of increase in age corresponded to a hazard ratio (HR) of 1.28 (95% CI 1.00‐1.65, P = .050); each increment of 803 ng/L of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) corresponded to a HR of 1.24 (95% CI 1.11‐1.39, P < .001); each increment of 58 ng/L of interleukin (IL)‐6 corresponded to a HR of 1.23 (95% CI 1.09‐1.40, P < .001), and each increment of 250 U/L of lactate dehydrogenase (LDH) corresponded to a HR of 1.23 (95% CI 1.10‐1.37, P < .001). According to the calculated cut‐points for age (≥70 years), NT‐proBNP (≥803 ng/L), IL‐6 (≥58 ng/L) and LDH (≥371 U/L) when 2 out of these 4 were overcome, the HR was 2.96 (95% CI 1.97‐4.45, P < .001). Conclusion In COVID‐19 patients, besides age, the evaluation of three biochemical parameters, available in few hours after hospital admission can predict in‐hospital mortality regardless of other comorbidities.