Background: The combination of capecitabine and oxaliplatin (CAPOX) is commonly used in patients with localized colorectal cancer (CRC) receiving curative-intent treatment. However, real-world data on the tolerability of CAPOX in this patient population are limited. This study aimed to assess the tolerability of CAPOX in a single-institution cohort of patients with localized CRC. Methods: A retrospective analysis was conducted using our institutional pharmacy database to identify patients with localized CRC who received neoadjuvant or adjuvant CAPOX. Demographic information, clinical characteristics, and treatment details were extracted from electronic health records. The primary endpoint was the rate of treatment completion, defined as the receipt of all planned chemotherapy cycles at full dosage, for both the overall cohort and patients aged 65 and above. Secondary outcome measures included the rate of grade 3 or higher adverse events, the frequency of hospital admissions due to CAPOX-related toxicities, and dose reductions. Results: A total of 153 patients were included in the analysis, with a median age of 61 years (range 32-84). Among them, 49% were female, 78.4% had stage III CRC, and the remaining had stage II disease. The racial distribution was 81% White and 15.7% Black. The proportion of patients who completed all planned CAPOX doses was 55.5% (85/153) in the entire cohort and 38% (23/60) in patients aged 65 and above (p = 0.22). Among patients intended to receive 4 cycles of CAPOX, only 57% (37/65) completed all 4 cycles. Female patients were less likely to complete treatment than male patients (p = 0.01). Dose reductions for oxaliplatin and capecitabine were observed in 37% (57/153) and 39% (59/153) of patients, respectively. Hospitalizations related to CAPOX-induced toxicities occurred in 18% (27/153) of patients, and 31% (47/153) experienced grade 3 or higher adverse events. A switch to FOLFOX was observed in 5% (8/153) of patients. Conclusions: This study highlights that a substantial number of patients with localized CRC undergoing curative-intent treatment with CAPOX do not complete the planned courses, potentially impacting their overall survival. Moreover, a significant proportion of patients experience grade 3 or higher toxicities with CAPOX, necessitating hospital admissions. These findings underscore the need for careful patient selection and management strategies to optimize the therapeutic benefits of CAPOX in this setting.