Background: The objective of this study was to examine the incidence and predictors of gastrointestinal (GI) complications following intensity-modulated radiation therapy (IMRT) for prostate cancer and their impact on national healthcare expenditure. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data, we identified 11,781 men diagnosed with non-metastatic prostate cancer from 2002 to 2006 who underwent definitive IMRT, had no pre-existing GI toxicity, and had at least 36 months of follow-up after IMRT initiation. Annual incremental spending was defined as the difference between the total Medicare payments in the year after the development of the first GI complication and the total Medicare payments in the year preceding prostate cancer diagnosis, excluding prostate cancer treatment-related costs. We used multivariate logistic regression to evaluate the odds ratio of developing IMRT-related GI toxicity, and quantile regression to compare the annual incremental costs between groups. All analyses were done using SAS 9.3. Results: Over the 36-month follow-up period, the incidence of post-IMRT GI complications was 26.5% (n=3,118). Patients on anti-coagulation therapy or receiving brachytherapy boost were more likely to develop IMRT-related GI toxicities (OR 1.11, 95% CI 1.01-1.22 (p=0.029) and OR 1.18, 95% CI 1.08-1.30 (p<0.001), respectively). The median Medicare annual incremental cost per patient associated with post-IMRT GI complications was $3,375 in 2014 dollars (95% CI $3,222-3,529, p<0.0001). Among patients with post-IMRT GI complications, the presence of diabetes was associated with an additional $610 (95% CI $206-1,014, p=0.003) per patient in Medicare spending. Conclusions: Medicare spending associated with post-IMRT GI complications is considerable, often in excess of 10% of IMRT cost. Quantifying these expenditures may better frame the potential for cost savings of emerging technologies that aim to reduce the incidence and severity of IMRT-related GI toxicities.