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Background: Keloids are less responsive to any single treatment modality; hence, there is a need for combination therapy that can yield satisfactory outcomes. Objective: The present study assessed efficacy and safety of combination therapy--surgical excision or cryotherapy and intralesional corticosteroids along with 5-fluorouracil [IL (S + 5-FU)] injection, followed by silicone gel sheet (SGS) under compression therapy in the treatment of keloids. Materials and Methods: This was a retrospective, observational study comprising 21 clinically diagnosed keloid patients. All patients were treated with the stated combination therapy. Data about demographic, lesions, procedural characteristics, and treatment outcomes were reported. Results: Of 21, 11 (52.4%) patients were treated with liquid nitrogen (LN2) cryotherapy, and 10 (47.6%) patients were treated with surgical excision. Mean age was 30.8 ± 7.6 (range: 14-44) years with slight male (52.4%) predominance. A mean surface area of keloid lesion was 96.8 ± 170.5 cm3. The most frequently involved site was auricle (8 [38.1%] patients). Patients received the following types of treatments: intralesional LN2 cryotherapy (6 [28.6%]), intralesional excisional surgery (6 [28.6%]), surface LN2 cryotherapy (5 [23.8%]), and extralesional excisional surgery (4 [19.0%]). Complications of recurrence (2 [9.5%]), secondary infections (2 [9.5%]), persistent postinflammatory hypopigmentation (1 [4.8%]), and atrophic scarring with postinflammatory hyperpigmentation (1 [4.8%]) were reported. After a study period of 2.5 years, 100% cure rate was achieved. Conclusion: Combination therapy of surgical excision or cryotherapy and IL (S + 5-FU), followed by SGS under compression, was safe and effective in treating keloids. [ABSTRACT FROM AUTHOR]