【】 Objective: To evaluate the efficacy and safety of different concentrations of 5-fluorouracil (5-FU) combined with compound betamethasone in the treatment of pathological scars. Methods: A total of 80 patients with pathological scars in the chest area, admitted between September 2023 and September 2024, were enrolled and randomly allocated into four groups (20 patients per group). Each group received intralesional injections of a suspension containing 5-FU at prepared concentrations of 6.3 mg/mL (low-concentration group), 12.6 mg/mL (medium-concentration group), 25.2 mg/mL (medium-high concentration group), or 50 mg/mL (high-concentration group), respectively, in combination with compound betamethasone. Evaluations were conducted at 1, 3, 6, and 12 months post-treatment, assessing clinical outcomes (rated as cured, markedly effective, effective, or ineffective), Vancouver Scar Scale (VSS) scores, and the incidence of adverse reactions. Results: No statistically significant differences were observed in gender, age, disease duration, or scar type among the four groups. The total effective rates showed no statistically significant differences at 1, 3, and 6 months post-treatment (all P > 0.05), but a statistically significant difference emerged at the 1-year mark (P < 0.05). Statistically significant differences were found among the four groups at all evaluated time points—1 month, 3 months, 6 months, and 1 year (all P < 0.05). Furthermore, the incidence rates of acne, folliculitis, osteoporosis, hematopoietic suppression, and the overall adverse reaction rate significantly differed among the groups (all P < 0.05). Conclusion: The combination of 5-FU and compound betamethasone demonstrates significant efficacy in treating pathological scars. While higher concentrations of 5-FU are associated with superior long-term outcomes, they also lead to an increased incidence of adverse reactions.