Background: TWEAK is an inflammatory cytokine which is involved in the development of many inflammatory disorders. Aims: This study aimed to evaluate serum levels of TWEAK in patients with acne vulgaris. Subjects and Methods: This case‐controlled study included 100 acne vulgaris patients divided into two groups. Group 1 included 25 patients with moderate acne and 25 patients with severe acne. Group 2 consisted of 50 acne‐free control subjects. Acne was graded by the Global Acne Grading System (GAGS). Serum TWEAK was measured by ELISA kits. Results: Acne patients had significant elevation in TWEAK serum levels when compared to the control subjects (P < 0.001). TWEAK serum levels did not show significant difference regarding disease grade, postacne scar, and hyperpigmentation (P value = 0.43, 0.37, 0.80, 0.67, respectively). TWEAK levels were not affected by any of the studied variables except for the significant negative correlation between its levels and the disease duration in severe acne group only (r = −0.42, P = 0.03). Conclusion: TWEAK may be involved in acne vulgaris development, but more studies are needed to clarify its role.