Diclofenac (DCLF) is one of the most widely prescribed non-steroidal anti-inflammatory drugs (NSAIDs). DCLF is associated with rare but serious idiosyncratic drug-induced liver injury (IDILI) in humans. It ranges from asymptomatic increase of plasma transaminases to life-threatening fulminant hepatitis with the need for liver transplantation. Mechanisms of DCLF-induced IDILI are not yet clarified, but immune responses are suspected to underlie them. In general, it is believed that women exhibit worse outcomes from DILI than men. The aim of this study is to investigate the involvement of immune reaction in mediating DCLF- hepatotoxicity and to evaluate the exacerbative effect of progesterone on DCLF-IDILI. The study was conducted on 100 albino mice divided into 5 main groups; each group was subdivided into a (female subgroup) and b (male subgroup) each of 10 mice; group I (negative control group), group II (normal saline group), group III (progesterone group), group IV (DCLF group), group V (progesterone and DCLF group). Results: DCLF administration, either alone or following progesterone, induced liver toxicity as manifested by abnormalities of hepatic profile (AST, ALT, T.Bil and GGT) together with increased plasma level of immune cytokine interlukin-1beta (IL-1β), with significant higher results encountered in females compared to males. Progesterone pre-treatment led to augmentation of the afro-mentioned indices in female mice only. These changes were substantiated with histopathological observations. From the previous results it can be concluded that an immune factor such as IL-1β is implicated in acute DCLF-induced hepatotoxicity and progesterone inflicts an exacerbative effect on this toxicity.