Background: Tramadol is a synthetic opioid analgesic. It is commonly prescribed for moderate to severe pain, becoming abused more popular among teens in most countries. Paracetamol as anti-inflammatory drugs (acetaminophen) (APAP) is widely used as an analgesic and antipyretic agent. Meanwhile, tramadol/acetaminophen (tramacet) is effective in acute or chronic moderate-to-moderately severe pain. In comparative study, the current investigation threw the light on the effect of over doses of tramadol and/or APAP on the immune function and hepatocytes in adult maleSprague-Dawley rats.   Material and methods: Treated rats received oral doses of each drug for 15 consecutive days and after last treatment, they kept three days later for withdrawal studies. The rats were divided into four treatment groups, in the first group, rats received saline and used as control. The second, third and fourth groups treated with tramadol (45 mg/kg), tramadol/APAP (45/450 mg/kg), APAP             (450 mg/kg) respectively, once a-day at the first week and ending with 90, 90/900, 900 mg/kg at the second week. Rats were sacrificed at the end of the first, second weeks and three days of last treatment.   Results: Daily doses of tramadol and /or APAP exposure in rats decreased the cellularity of spleen. Moreover, phagocytic and killing of S. aureus by PMN and macrophage cells caused  a highly significant decrease in treated groups. IFN-γ was reduced in a statistically different treated group of rats. Serum IL-10 was unaffected by any of the treatment regimens but increased only in tramadol/APAP treated rats. Spleen histology exhibited mild pathological alteration with different injures between treated groups. Splenic white pulp accompanied by ill deformed which reflected the reduction of white pulp zones, thickened vasculature in the splenic net work, fibrous trabeculae become prominent feature, where splenic red pulp occupied large areas of the splenic network with predominant edema and megakaryocytes. On the other hand, the effect of tramadol and/or APAP induced DNA alterations of hepatocytes in dose dependent pattern as elucidated by dendrogramatic analysis. Liver histopathological changes of treated groups included vacuolated hepatocytes, dilated sinusoid with proliferated Kupffer cells; atrophied hepatocytes with nuclei reduced in size and darkly stained. Many areas of hepatocytes showed loss of architecture, congested central vein, expanded portal area with edema and inflammatory reaction.   Conclusion:             It could be concluded that the effect of tramadol/APAP induced anti-inflammatory cytokines than tramadol and APAP alone. Tramadol and/or APAP may display severe pathological consequences of hepatocytes. These hepatic lesions may be caused impairment of the liver function.