Background: Hepatic pedicle clamping (HPC) is frequently used to minimize blood loss during liver parenchymal transection in patients undergoing hepatectomy; this may cause intestinal hypoperfusion and is considered a possible risk factor for colonic anastomotic leak. The objective of this study is to determine the effect of HPC on the risk of colonic anastomotic leak in patients undergoing combined hepatectomy and colectomy. Methods: Patients undergoing combined hepatectomy and colectomy between 2014 and 2018 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Organ space infection was used as a surrogate marker for colonic anastomotic leak. We performed 1:1 coarsened exact matching for age, body mass index, American Society of Anesthesiology score, diabetes, smoking, wound class, type of colectomy, type of hepatectomy, and creation of a diverting stoma. Multivariable logistic regression of the unmatched patient cohort was also performed adjusting for the same covariates. Results: We identified 549 patients, of whom 130 (23%) underwent HPC during the study period. Ninety-one patients (17%) had organ space infections. Among 218 patients in the matched cohort, there was no difference in organ space infections among patients with or without HPC (17.4%, 95% confidence interval CI 10.2-24.6 v. 14.7%, 95% CI 7.9-21.4, p = 0.58). Similarly, there was no difference in the odds of organ space infection in patients with and without HPC on multivariable logistic regression (odds ratio 1.1, 95% CI 0.64-1.91, p = 0.72). HPC was not associated with organ space infection, which covaries with colonic anastomotic leak, in patients undergoing combined hepatectomy and colectomy. Conclusion: Prospective studies are needed to determine the safe duration and technique (i.e., intermittent or continuous) of HPC in this patient population.