Objective: This systematic review and meta-analysis addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. Data Sources: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS, and unpublished sources for randomized controlled trials that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. Study Selection: Reviewers conducted duplicate screening of citations, data abstraction, and, using a modified Cochrane risk of bias tool, individual study risk of bias assessment. Data Extraction: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. We assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random-effect models. For subgroup analyses, we performed metaregression and considered p value less than 0.05 as significant. Data Synthesis: Forty-two randomized controlled trials including 10,194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28–31 d) (relative risk, 0.93; 95% CI, 0.84–1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase), and possibly achieve a small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, 0.89–1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference, –0.73 d; 95% CI, –1.78 to 0.31) and hospital (mean difference, –0.73 d; 95% CI, –2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12–1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, –1.39; 95% CI, –1.88 to –0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32–2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08–1.24) (moderate certainty), may increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, 1.01–1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest ( p > 0.05 for all). Conclusions: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.