Background: The association between sarcopenia (or muscle loss) and worse oncologic outcomes has been documented in several different cancers and is thought to be a potential marker of a diminished host response to tumor. The prognostic role of sarcopenia in rectal cancer (RC) patients has yet to be elucidated. We sought to examine the impact of radiologically-defined sarcopenia on outcomes of RC patients treated by neoadjuvant chemoradiation (NCR) and radical resection. Methods: Between 1998-2010, we identified 90 patients with stage II/III RC treated by NCR and radical surgery. Sarcopenia was assessed using 3 CT-based measures derived at the L4-L5 level including mean psoas density (MPD; Hounsfield Units), total psoas area (TPA; mm²) and muscle mass index (MMI=TPA/height²; mm²/m²). Clinicopathologic data (age, gender, pretreatment and final tumor stage, treatment response and CEA level) were collected. Associations were analyzed by Wilcoxon Rank Sum while the Kaplan–Meier method, log-rank test, and Cox proportional hazards models were used to evaluate overall survival (OS) and disease-free survival (DFS). Results: Our population consisted of 50 males and 40 females with a median age at diagnosis of 61 (range 35-87). By univariate analyses, only age >61 was associated with the presence of sarcopenia by all 3 measures [MPD (p=0.0003), MMI (p=0.0001), and TPA (p=0.0008)]. Female gender was associated with increased muscle loss by MMI (p<0.0001) and TPA (p<0.0001). By Cox multivariate analysis, MPD (range 14.5-77.3 HU) was independently associated with a worse OS (AHR= 0.94; 95% CI, 0.88-0.99; p= 0.04) and marginally associated with DFS (AHR= 0.95; 95% CI, 0.89-1.00; p= 0.056) when controlling for age, gender and pathologic response. This translates to a 28.5% reduction in risk of death with every 5 HU decrease in MPD. Conclusions: We have demonstrated that pre-treatment sarcopenia as measured by MPD is associated with worse OS and possibly DFS in patients with RC treated by NCR and radical surgery. Larger scale studies of sarcopenia and RC are warranted. Strategies targeting reversal of processes associated with muscle loss may play a potential future role in the multidisciplinary management of rectal cancer.