The aim of this study was to determine the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use on incident sepsis and other severe infections.We searched PubMed, EMBASE, CENTRAL, and ClinicalTrial.gov up to September 14, 2021, for double-blind, placebo-controlled randomized trials of alirocumab, evolocumab, or inclisiran with >100 participants in each arm and report of serious adverse events related to infection. Data were synthesized with the fixed-effect Mantel-Haenszel model to generate risk ratios (RRs) with 95% confidence intervals (CIs) of each outcome for PCSK9 inhibitor versus placebo. Main outcome was sepsis. Other outcomes were total severe infections, severe bacterial and viral infections, and severe organ system-specific infections including respiratory tract, gastrointestinal, and genitourinary tract infections.A total of 20 studies of 64,984 participants were included (alirocumab: n = 7; evolocumab: n = 9; inclisiran: n = 4). Sepsis was reported in 292 (0.51%) participants from 11 trials (PCSK9 inhibitor 0.47%; placebo 0.56%). PCSK9 inhibitor use was not associated with risk of sepsis compared with placebo (Summary RR: 0.85, 95% CI: 0.67-1.07, P = .16); nor was it associated with any severe infection (0.96, 95% CI: 0.89-1.03), severe bacterial (0.96, 95% CI: 0.81-1.14) and viral infections (1.01, 95% CI: 0.77-1.33); nor with any severe organ system-specific infection (all P values >.05). The between-study heterogeneity in all analyses was small.There was neither a beneficial nor a harmful association between PCSK9 inhibitors and risk of sepsis or severe infections. These findings provide reassurance regarding the safety of PCSK9 inhibitors in patients who are concerned about potential drug side effects related to infections.