OBJECTIVE Central-line-associated bloodstream infections (CLABSI) are an important cause of morbidity and mortality in neonates. We aimed to determine whether intra-abdominal pathologies are an independent risk factor for CLABSI. METHODS We performed a retrospective matched case-control study of infants admitted to the neonatal intensive care units (NICUs) of the Montreal Children's Hospital (Montreal) and the Royal Alexandra Hospital, Edmonton, Canada. CLABSI cases that occurred between April 2009 and March 2014 were identified through local infection control databases. For each case, up to 3 controls were matched (National Healthcare Safety Network [NHSN] birth weight category, chronological age, and central venous catheter (CVC) dwell time at the time of CLABSI onset). Data were analyzed using conditional logistic regression. RESULTS We identified 120 cases and 293 controls. According to a matched univariate analysis, the following variables were significant risk factors for CLABSI: active intra-abdominal pathology (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.8-6.4), abdominal surgery in the prior 7 days (OR, 3.5; 95% CI, 1.0-10.9); male sex (OR, 1.7; 95% CI, 1.1-2.6) and ≥3 heel punctures (OR, 4.0; 95% CI, 1.9-8.3). According to a multivariate matched analysis, intra-abdominal pathology (OR, 5.9; 95% CI, 2.5-14.1), and ≥3 heel punctures (OR, 5.4; 95% CI, 2.4-12.2) remained independent risk factors for CLABSI. CONCLUSION The presence of an active intra-abdominal pathology increased the risk of CLABSI by almost 6-fold. Similar to CLABSI in oncology patients, a subgroup of CLABSI with mucosal barrier injury should be considered for infants in the NICU with active intra-abdominal pathology. Infect Control Hosp Epidemiol 2016;1446-1452.