To identify factors associated with the risk of death in adolescent and adult inpatients with laboratory-positive (reverse-transcription polymerase chain reaction) influenza in Mexico during consecutive influenza seasons (2018-2020).A retrospective cohort study used national surveillance system data, enrolling 3.422 individuals. The association between various risk factors and 30-day in-hospital lethality were evaluated through risk ratios (RRs) and 95% confidence intervals (CIs).The lethality rate was 18.1%. Flu vaccination history (RR=0.56, 95% CI 0.42-0.78), early antiviral drug administration (≤2 days from symptom onset [reference ≥5 days], RR=0.68, 95% CI 0.58-0.81), and a history of asthma (RR=0.66, 95% CI 0.47-0.95) showed protective effects against influenza-attributable death. Mechanical ventilator support produced the highest increase in death risk (RR=3.31, 95% CI 2.89-3.79). Male sex, older age, AH1N1 subtype, and other chronic diseases were also associated with fatal in-hospital influenza-related outcomes.Our findings highlight the major relevance of promoting immunization in high-risk individuals, together with ensuring early and effective antiviral management in suspected influenza cases.Copyright © 2020 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.