Background: Substance abuse is a worldwide problem with rapidly expanding prevalence. Liver is highly vulnerable to xenobiotics toxicities. Methods: We have investigated the effect of substances of 5 commonly abused in Egypt (tramadol, opiates, cannabis, barbiturates and benzodiazepines) on liver functions in persons attending to Mansoura university hospitals. After exclusion of cases with chronic liver diseases, participants were screened by enzyme multiplied immunoassay. Positive cases were confirmed by gas chromatography-mass spectroscopy and examined by abdominal ultrsonography and live functions tests were done. Results: GC-MS showed only 125 positive cases. No abnormalities were detected by ultrasonography in the examined populations. SGOT, SGPT and direct bilirubin were significantly increased, while albumin was significantly decreased in abusers in comparison to nonabusers. Tramadol and other opioids were shown to be the most hepatotoixc agents. In addition, SGOT was shown to be significantly increased to less extent in tramadol and cannabis co-abusers. Furthermore, benzodiazepines were shown to significantly increase serum direct and total bilirubin. Conclusions: We can conclude that tramadol and other opioids significantly alter liver synthetic and excretory function in parallel to significant increase in liver enzymes among abusers. Moreover, cholestatic hepatitis was observed among benzodiazepine abusers.