Background and Objectives: Conventional long-course radiotherapy (LCRT) and a new paradigm of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) are used in locally advanced rectal cancer (RC). There are few economic assessment reports available on TNT that focus on cost analysis in a country with limited funding for healthcare systems. The objective of this study was to perform a cost analysis comparing SCRTTNT versus LCRT. Materials and Methods: In 2020-2021, a prospective registry was created to document RC patients who received neoadjuvant therapy and the costs of cancer treatments, transportation and the time patients and family members spent in the hospital. This registry outlined the direct and indirect costs of LCRT versus SCRT-TNT. Results: LCRT and SCRT-TNT regimens have direct costs that range from S/.5,993.30 to S/.27,928.36 and from S/.3,409.81 to S/.18,159.42, respectively. FOLFOX regimens are the most expensive. Administering radiotherapy in 28 3D sessions and 5 sessions of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) sessions costs S/.2,603.88, S/.1,277.19 and S/.1,027.77, respectively. The indirect cost of FOLFOX regimens is twice that of the similar modality that combines irradiation and Oxaliplatin IV and Capecitabine VO (CAPOX). SCRT-TNT regimens with CAPOX reduce costs by at least 50%, while SCRT-TNT regimens with FOLFOX reduce costs by 32%. Conclusion: Despite using IMRT/VMAT, SCRT-TNT is a less expensive approach for patients with RC when compared to LCRT. The costs to patients using SCRT-TNT are much lower, but it is also a better option because it saves hospital resources. Copyright: