Background: High-mobility group box 1 (HMGB1)-receptor for advanced glycation end (RAGE)-moesin axis could be implicated in induction of inflammation. However, there is a scarcity in literature discussing the role of this axis in inflammatory skin disorders. Aims: The aim of the present study was to evaluate the serum levels of HMGB1 and moesin in patients with inflammatory acne vulgaris. Patients/Methods: This comparative cross-sectional study included 66 inflammatory acne vulgaris patients classified according to Global Acne Grading System (GAGS) into three groups (22 patients each): mild, moderate, and severe acne vulgaris. In addition, 82 acne-free individuals were included as a control group. Serum HMGB 1 and moesin levels were measured using enzyme-linked immunosorbent assay kits. Results: High-mobility group box 1 and moe sin serum levels in acne patients were significantly higher than the levels in control subjects (p = 0.04, 0.0005 respectively). Serum levels of both markers in severe acne patients and in those with post-acne scarring were elevated when compared to the levels in the other groups, and however, this elevation was significant only for moesin levels. There was a significant positive correlation between the serum levels of HMGB1 and moesin in the studied patient's sample (r = 0.3079, p = 0.011). Conclusion: High-mobility group box 1-receptor for advanced glycation end-moesin axis may be implicated in acne vulgaris pathogenesis, and it may be a promising therapeutic target.