This study aimed to evaluate the histochemical changes in the liver and protein changes in the serum, induced by combination of paracetamol (analgesic and antipyretic drug) and caffeine in female rats. Female rats were divided into four groups, the first group served as control, the second received multiple oral doses of paracetamol and caffeine (125 and 20 mg/kg bw, respectively), the third group received oral dose of paracetamol and caffeine (250 and 40 mg/kg bw, respectively) and the fourth received oral dose of paracetamol and caffeine (500 and 75 mg/kg bw, respectively). The treatment lasted for four weeks. The obtained results showed that this combination caused different histological changes and caused significant diminutions in the contents of total protein, nuclear DNA and esterase enzyme in the liver. Also the treatments with this combination discomfort the normal protein patterns of serum in comparison with control. These effects were evidently dose dependent. These results support the suggestion that the previously known effect of the analgesic drug may be enhanced with caffeine administration.