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Inducing collagen synthesis and remodeling is crucial to achieving optimal clinical improvement in acne scar treatment. Cell therapy with autologous fibroblast can be an alternative treatment option for depressive acne scars. The objective was to investigate the effect of autologous fibroblast treatment of moderate to severely depressed acne scars, a 6month prospective, a randomized control study was performed at tertiary medical centers. This study was conducted based on a 6-month, prospective, randomized controlled study to compare the effect of autologous fibroblast injection for atrophic acne scar. Patients were randomized to receive either autologous fibroblasts or vehicle control (protein-free cell culture medium). They were treated with three sessions of intradermal injection of either autologous fibroblast suspension or control cell culture medium on each side of the cheek, with a 2-week interval. At 3 and 6 months after the last treatment, the patients returned for follow-up visits. The improvement rate of the acne scar severity measured by 7-point photoguide scale and échelle d'évaluation clinique des cicatrices d'acné (ECCA). A total of 136 patients were enrolled to the study (autologous fibroblast, n ¼ 64; control, n ¼ 64). The treatment group reported a statistically significant improvement rate in acne scar scores rated using the 7-point photoguide scale (p < 0.0001). According to ECCA, both groups reported significant improvements, but the improvement rates between the two groups did not show a significant difference. The patient-reported outcome was superior in the autologous fibroblast treatment group. No significant adverse effects were observed throughout the follow-up periods. This study demonstrated that autologous fibroblasts resulted in significant improvement in the appearance of acne scars with minimal treatment-related adverse events.