Background: In addition to lowering lipid levels and treating atherosclerotic disease, statins have demonstrated anti-inflammatory and anti-tumor activity in various cancer types. We evaluate this effect in esophageal cancer patients undergoing esophagectomy. Methods: All patients undergoing esophagectomy for esophageal cancer at Roswell Park Comprehensive Cancer Center between March 2007 and December 2015 were included. The association between pre-surgery statin use with overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression, with age, sex, American Society of Anesthesia (ASA) score, neoadjuvant therapy, surgical technique, tumor stage, histology, and grade considered in multivariable analyses. Survival analyses were independently performed for body mass index (BMI)-based patient subgroups. Results: 212 patients met inclusion criteria for this study. Median follow up period was 36 months. Estimated five-year RFS for the patient cohort overall was 55.7% and estimated five-year DSS was 53.9%. Estimated five-year OS was 45.4%. There was no significant association between statin use and outcomes of esophagectomy patients overall. However, in subgroup analysis analyzing patients by BMI category, there was a significant association between statin use and outcomes in patients with BMI ≥ 30 (n = 95 patients). Multivariate analysis in obese patients demonstrated an association of statins with improved OS (HR 0.52, p = 0.049), DSS (HR 0.46, p = 0.034) and RFS (HR 0.43, p = 0.036). The other variables significantly associated with outcome measures were stage ≥ 2 (OS HR 2.36, p = 0.010; RFS HR 2.50, p = 0.018; DSS HR 2.51, p = 0.011) and ASA score ≥ 3 (RFS HR 2.26, p = 0.037; DSS HR 2.33, p = 0.019). Conclusions: Statin use is associated with improved RFS, DSS and OS of obese patients undergoing esophagectomy for esophageal cancer. This novel finding suggests an interaction between the pathophysiologic state of obesity and the pleiotropic effects of statins. BMI could be explored as a potential biomarker for adjunctive statin use in future trials.