Background. Keloids cause cosmetic problems, pain, and pruritus. Different modes of therapy are limited by their efficacy and side effects. High-mobility group box 1 protein (HMGB1) may play a role in keloid pathogenesis; therefore, the therapeutic potential of box A1, an antireceptor of advanced glycation end products antibody, and other inhibitors of HMGB1 may play a role in the treatment of keloids. Objective. This study evaluates the role of HMGB1 in patients with keloids by comparing their serum level with healthy controls. Materials and Methods. Forty patients with keloids and 40 controls were enrolled in this study. Detailed history and clinical evaluation were performed. A 3-mL sample of whole blood was obtained from both patient groups and centrifuged immediately. The resultant supernatant serum was frozen at -20°C for the detection and quantification of HMGB1 using enzyme-linked immunosorbent assay. Results. There was a statistically significant elevation in the mean value of HMGB1 in keloid cases (74.38 ± 40.16) compared with the mean value of the controls (52.00 ± 5.41; P = .001). Mean value of HMGB1 was positively correlated with keloid severity. Conclusions. High-mobility group box 1 was found to be elevated in patients with keloids compared with their controls, suggesting its role in excessive scarring and the role of its antagonists in therapy.