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Background: Keloids and hypertrophic scars cause physical and psychosocial problems. A combination of 5-fluorouracil (5-FU) and triamcinolone acetonide (TAC) may enhance the treatment of pathologic scars, although the evidence base is limited. The authors compared the efficacy and complication rates of combination intralesional TAC and 5-FU with those of monotherapy intralesional TAC or 5-FU for the treatment of keloids and hypertrophic scars., Methods: Embase, MEDLINE, and CENTRAL were searched by two independent reviewers. The primary outcome was treatment efficacy (51% to 100% improvement). Study quality and risk of bias were assessed using the Cochrane risk of bias tool., Results: Of 277 articles screened, 13 studies were included, comprising 12 randomized control trials and one nonrandomized study. Six studies compared combination intralesional therapy versus monotherapy 5-FU, and nine studies compared combination intralesional therapy versus monotherapy TAC. The combined group demonstrated superior objective treatment efficacy compared with the monotherapy TAC group (OR, 3.45; 95% CI, 2.22 to 5.35; I 2 = 0%; P < 0.00001) and monotherapy 5-FU group (OR, 4.17; 95% CI, 2.21 to 7.87; I 2 = 0%; P < 0.0001). Telangiectasia was less frequent in combination therapy (OR, 0.24; 95% CI, 0.11 to 0.52; I 2 = 0%; P = 0.0003) compared with monotherapy TAC., Conclusions: Combined intralesional TAC and 5-FU administration demonstrated superior treatment efficacy outcomes compared with monotherapy TAC or 5-FU. Patient-reported outcome measures should be incorporated in the design of future research to justify clinical recommendations., Clinical Relevance Statement: Combined TAC and 5-FU has demonstrated superior treatment efficacy outcomes compared to monotherapy TAC or 5-FU in the treatment of hypertrophic scars and keloids., (Copyright © 2023 by the American Society of Plastic Surgeons.)