Drug addicts are prone to infection with viruses including hepatitis-B and HIV. Besides indirect effects as a consequence of lifestyle, heroin and methadone may also enhance the risk of infections by a direct immunotoxic effect affecting resistance. In addition to general toxicological screening, we therefore performed a screening for potential immunotoxicity of morphine and methadone. Rats treated orally with different dosages of morphine or methadone for 6 weeks showed only a minor effect of overt toxicity on liver and spleen at the high dose, whereas at lower doses an increase in the relative weight of the mesenteric lymph nodes and an increase in cell density in the medullary cords were observed histopathologically, indicating a specific effect on humoral immunity. This specific immunotoxic effect was corroborated by an increased IgG concentration in serum (significant for the methadone-treated group). Further immunotoxicological research is needed aimed at revealing the potential risk of opiate use with respect to immune function. In conclusion, the present paper showed the toxicological profile of morphine and methadone in an extended 28 day subchronic study. Specific immunotoxicological effects were observed at doses where no effects were seen in routine toxicological evaluation, suggesting that the immune system is sensitive to opiates.