Importance: Intravascular catheters are essential in health care but remain a major source of health care-associated infections. Optimal skin antisepsis before insertion is key, yet the most effective antiseptic agent, concentration, and formulation remain uncertain.

Objective: To determine the concentration and formulation of chlorhexidine gluconate (CHG) or povidone-iodine (PVI) associated with the lowest incidence of catheter-related infections (CRIs).

Data sources: PubMed, EMBASE, Cochrane Central, Scopus, Web of Science, and CINAHL were searched through January 7, 2025, without restrictions. Trial registries and reference lists of relevant studies and guidelines were reviewed.

Study selection: Randomized clinical trials (RCTs) comparing CHG- or PVI-based skin antisepsis before insertion of intravascular catheters were eligible if they reported at least 1 CRI outcome (catheter-related bloodstream infection [CRBSI], catheter tip colonization, or local infection). Two independent reviewers screened titles, abstracts, and full texts.

Data extraction and synthesis: Data were extracted independently by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk of bias was assessed with the Cochrane risk of bias 2 tool. A random-effects network meta-analysis (NMA) was performed to estimate relative risks (RRs) with 95% CIs.

Main outcomes and measures: The primary outcomes were incidence of CRBSIs, catheter tip colonization, and local infections associated with CHG or PVI formulations.

Results: Sixteen RCTs (7803 patients; 11 985 catheters) met inclusion criteria. When compared with aqueous formulations, alcohol-based formulations were consistently associated with lower infections rates, with isopropyl alcohol being superior to ethanol. Compared with alcoholic PVI, alcoholic CHG was associated with lower CRBSIs (RR, 0.70 [95% CI, 0.45 to 1.08]), catheter tip colonizations (RR, 0.42 [95% CI, 0.37 to 0.48]), and local infections (RR, 0.40 [95% CI, 0.23 to 0.70]). High concentration CHG (1% or higher) further lowered CRBSIs (RR, 0.31 [95% CI, 0.19 to 0.52]) and colonization (RR, 0.36 [95% CI, 0.30 to 0.42]) compared with lower concentrations. Local adverse events were uncommon, slightly more frequent with alcohol-based formulations, and similar between CHG and PVI.

Conclusions and relevance: In this NMA of RCTs, high concentration CHG in isopropyl alcohol was associated with the lowest incidence of CRIs. These results suggest that alcoholic PVI and aqueous formulations should be reserved for situations in which CHG or alcohol cannot be used.