Abstract Objective: To identify central-line (CL)–associated bloodstream infection (CLABSI) incidence and risk factors in low- and middle-income countries (LMICs). Design: From July 1, 1998, to February 12, 2022, we conducted a multinational multicenter prospective cohort study using online standardized surveillance system and unified forms. Setting: The study included 728 ICUs of 286 hospitals in 147 cities in 41 African, Asian, Eastern European, Latin American, and Middle Eastern countries. Patients: In total, 278,241 patients followed during 1,815,043 patient days acquired 3,537 CLABSIs. Methods: For the CLABSI rate, we used CL days as the denominator and the number of CLABSIs as the numerator. Using multiple logistic regression, outcomes are shown as adjusted odds ratios (aORs). Results: The pooled CLABSI rate was 4.82 CLABSIs per 1,000 CL days, which is significantly higher than that reported by the Centers for Disease Control and Prevention National Healthcare Safety Network (CDC NHSN). We analyzed 11 variables, and the following variables were independently and significantly associated with CLABSI: length of stay (LOS), risk increasing 3% daily (aOR, 1.03; 95% CI, 1.03–1.04; P < .0001), number of CL days, risk increasing 4% per CL day (aOR, 1.04; 95% CI, 1.03–1.04; P < .0001), surgical hospitalization (aOR, 1.12; 95% CI, 1.03–1.21; P < .0001), tracheostomy use (aOR, 1.52; 95% CI, 1.23–1.88; P < .0001), hospitalization at a publicly owned facility (aOR, 3.04; 95% CI, 2.31–4.01; P <.0001) or at a teaching hospital (aOR, 2.91; 95% CI, 2.22–3.83; P < .0001), hospitalization in a middle-income country (aOR, 2.41; 95% CI, 2.09–2.77; P < .0001). The ICU type with highest risk was adult oncology (aOR, 4.35; 95% CI, 3.11–6.09; P < .0001), followed by pediatric oncology (aOR, 2.51;95% CI, 1.57–3.99; P < .0001), and pediatric (aOR, 2.34; 95% CI, 1.81–3.01; P < .0001). The CL type with the highest risk was internal-jugular (aOR, 3.01; 95% CI, 2.71–3.33; P < .0001), followed by femoral (aOR, 2.29; 95% CI, 1.96–2.68; P < .0001). Peripherally inserted central catheter (PICC) was the CL with the lowest CLABSI risk (aOR, 1.48; 95% CI, 1.02–2.18; P = .04). Conclusions: The following CLABSI risk factors are unlikely to change: country income level, facility ownership, hospitalization type, and ICU type. These findings suggest a focus on reducing LOS, CL days, and tracheostomy; using PICC instead of internal-jugular or femoral CL; and implementing evidence-based CLABSI prevention recommendations.