Background: Acne is an inflammatory skin condition of pilosebaceous unit. Its pathogenesis is multifactorial with a central role of inflammatory and pro-inflammatory cytokines mediators. Downregulated Kruppel-like factor 2 (KLF2) leads to rapid secretion of many cytokines that are involved in acne pathogenesis. Aims: This study aimed at evaluating the level of KLF2 mRNA, clarifying its role in acne pathogenesis and its relation to acne lesion type, degree of severity, and outcome. Patients and Methods: The level of KLF2 mRNA was measured in 100 patients with acne and 50 age- and sex-matched healthy controls by using quantitative real-time polymerase chain reaction (qRT-PCR). Results: The value of KLF2 mRNA was lower in acne patients than control group (P < .001), being lowest in inflammatory acne group (grades III, IV, and V) than noninflammatory acne group (grades I and II) and highest in the control group (P < .001). KLF2 mRNA was decreased significantly with increased acne severity grade (P < .001). KLF2 mRNA was lower in cases healed by scars than those healed by postinflammatory hyperpigmentation. Conclusions: Decreased serum level of KLF2 is not only a claimed for AV pathogenesis but also a predictor for degree of acne severity and outcome.