Abstract Background There is currently no single treatment that mitigates all harms caused by severe acute respiratory syndrome coronavirus 2 infection. Tocilizumab, an interleukin-6 antagonist, may have a role as an adjunctive immune-modulating therapy. Methods This was an observational retrospective study of hospitalized adult patients with confirmed coronavirus disease 2019 (COVID-19). The intervention group comprised patients who received tocilizumab; the comparator arm was drawn from patients who did not receive tocilizumab. The primary outcome was all-cause mortality censored at 28 days; secondary outcomes were all-cause mortality at discharge, time to clinical improvement, and rates of secondary infections. Marginal structural Cox models via inverse probability treatment weights were applied to estimate the effect of tocilizumab. A time-dependent propensity score–matching method was used to generate a 1:1 match for tocilizumab recipients; infectious diseases experts then manually reviewed these matched charts to identify secondary infections. Results This analysis included 90 tocilizumab recipients and 1669 controls. Under the marginal structural Cox model, tocilizumab was associated with a 62% reduced hazard of death (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.21 to 0.70) and no change in time to clinical improvement (aHR, 1.13; 95% CI, 0.68 to 1.87). The 1:1 matched data set also showed a lower mortality rate (27.8% vs 34.4%) and reduced hazards of death (aHR, 0.47; 95% CI, 0.25 to 0.88). Elevated inflammatory markers were associated with reduced hazards of death among tocilizumab recipients compared with controls. Secondary infection rates were similar between the 2 groups. Conclusions Tocilizumab may provide benefit in a subgroup of patients hospitalized with COVID-19 who have elevated biomarkers of hyperinflammation, without increasing the risk of secondary infection.