OBJECTIVES: To confirm whether a relationship exists between male sex and coronavirus disease 2019 (COVID-19) mortality and whether this relationship is age dependent. PATIENTS AND METHODS: We queried the COVID-19 Research Network, a multinational database using the TriNetX network, to identify patients with confirmed COVID-19 infection. The main end point of the study was all-cause mortality. RESULTS: A total of 14,712 patients were included, of whom 6387 (43%) were men. Men were older (mean age, 55.0+/-17.7 years vs 51.1+/-17.9 years; P<.001) and had a higher prevalence of hypertension, diabetes, coronary disease, obstructive pulmonary disease, nicotine dependence, and heart failure but a lower prevalence of obesity. Before propensity score matching (PSM), all-cause mortality rate was 8.8% in men and 4.3% in women (odds ratio, 2.15; 95% CI, 1.87 to 2.46; P<.001) at a median follow-up duration of 34 and 32 days, respectively. In the Kaplan-Meier survival analysis, the cumulative probability of survival was significantly lower in men than in women (73% vs 86%; log-rank, P<.001). After PSM, all-cause mortality remained significantly higher in men than in women (8.13% vs 4.60%; odds ratio, 1.81; 95% CI, 1.55 to 2.11; P<.001). In the Kaplan-Meier survival analysis, the cumulative probability of survival remained significantly lower in men than in women (74% vs 86%; log-rank, P<.001). The cumulative probability of survival remained significantly lower in propensity score-matched men than in women after excluding patients younger than 50 years and those who were taking angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medications on admission. CONCLUSION: Among patients with COVID-19 infection, men had a significantly higher mortality than did women, and this difference was not completely explained by the higher prevalence of comorbidities in men.