Endoscopic submucosal dissection (ESD) is an effective method for removing early colorectal lesions. However, research on the safety and efficacy of ESD in patients with various underlying conditions remains limited. This study retrospectively examined ESD outcomes in colorectal neoplasm patients from five tertiary medical centers. The Charlson Comorbidity Index (CCI) and age-adjusted CCI (ACCI) were analyzed, and the differences in complete resection and complication rates were analyzed. The CCI, ACCI, and complication rates tended to gradually increase proportionally, and the complication resection rate increased from CCI 2 to ACCI 4 as the starting point, followed by a decreasing trend. Of these, 140 patients (9.7%) had a CCI score of 3 or higher. The high CCI group was older (70.6% vs. 64.7%, p < 0.01) and had a higher proportion of men (70.7% vs. 58.7%, p < 0.01) than the low CCI group. The high CCI group had a higher incidence of cancer than the low CCI group (77.9% vs. 65.2%, p < 0.01). The en bloc resection rate (90.0% vs. 89.3%, p = 0.79) and complete resection rate (75.7% vs. 81.2%, p = 0.12) were not significantly different between the two groups. Colorectal ESD can be safely and effectively performed in patients with various underlying medical conditions.