BACKGROUND This study examined the effects of khat extract on the proinflammatory cytokines, liver, and kidneys of rats. Unlike previous research that focused on broad immune markers and general effects, this study investigated specific proinflammatory cytokines (IL-1ß, IL-2, IL-4, IL-6, and TNF-alpha) and considered gender differences in the immune response. Fresh khat plants and nontoxic doses were used to obtain clear observations relevant to human health. MATERIAL AND METHODS Extracts were prepared from young shoots of khat plants and fresh leaves. 150-gram male and female rats were randomly divided into 8 groups (5 rats per group). Six groups received the extract orally for 8 weeks at doses of 100, 300, and 500 mg/kg/day. Blood samples were collected after 56 days and assayed for cytokines using ELISA, while liver enzymes and kidney markers were assayed using kinetics and colorimetric methods. RESULTS Khat extract increased the levels of most cytokines, with higher doses causing greater increase. This effect was consistent across sexes for some cytokines (IL-1ß, IL-2), but not others (IL-4, IL-6, TNF-alpha), where sex played a role at specific doses. Various doses of the extract influenced glucose levels in both male and female rats. In addition, liver enzyme markers showed some variations. CONCLUSIONS This study, with its intriguing findings, illuminates the complex effects of khat on various systems. Variations in AST and ALT levels in the liver support earlier hepatotoxicity research and suggest possible khat-induced damage. This study revealed consistently increased levels of all cytokines as the dose of khat extract increased.