Background: Treatment of keloids presents a significant therapeutic challenge due to their tendency to recur and their impact on a patient�s quality of life. This randomised controlled trial aimed to compare the effectiveness of intralesional triple combination regimen versus intralesional triamcinolone acetonide monotherapy in treating keloids. Aims: To compare the efficacy and safety of intralesional triple combination versus intralesional triamcinolone acetonide monotherapy in treating keloids at any site. Methods: This study was conducted in the outpatient department of Dermatology, Venereology and Leprosy in a tertiary care hospital at Puducherry. Seventy two patients aged �18 years with a clinical diagnosis of keloids of any duration, involving any site and without any prior treatment were included in the study. Patients were randomised into two groups: Group A received intralesional triple combination (triamcinolone acetonide, 5-fluorouracil and hyaluronidase), while Group B received intralesional triamcinolone acetonide monotherapy. Treatments were administered every three weeks for four sessions or till complete flattening, whichever was earlier. The Vancouver Scar Scale was used for assessment at baseline and every three weeks for four sessions, and monthly for three months post treatment. Results: Both groups showed significant improvement in the Vancouver Scar Scale scores at each follow-up compared to baseline. The mean (percentage) improvement in the Vancouver Scar Scale score in Group A was 0.58 ± 0.5 (7.08) at three weeks, which progressively increased to 4.47 ± 1.29 (54.55) at the final follow-up. In Group B, the improvement was lesser, with 0.08 ± 0.28 (0.95) at three weeks, increasing to 3.08 ± 0.81 (36.65) at the final follow-up. This improvement was significantly more in Group A at all time points compared to Group B (p < 0.05). Post-procedure pain, which lasted for a few hours, was noted in three and two patients in Groups A and B, respectively (p = 0.642). None of the patients had a recurrence of keloids during the study. Limitations: Limitations of this study include small sample size, single centre design, short follow-up period, lack of blinding and patient-reported outcome measures, which may impact the generalisability of the findings. Conclusion: Intralesional triple combination is more effective than triamcinolone acetonide monotherapy in treating keloids, offering significantly superior improvements in the Vancouver Scar Scale scoring. © 2025 Elsevier B.V., All rights reserved.