Morphine treatment has been shown to suppress several immunologic parameters. In this study, we examined the effects of morphine pellet implantation in vivo on the primary antibody response measured in vitro in various mouse strains. Effects of mouse strain and sex on morphine-induced suppression of the plaque-forming cell response, as well as spleen weight and mortality were determined. Morphine suppressed the primary antibody response in C3HeB/FeJ, C3H/HeJ and C57Bl/6 mice, while Balb/cByJ and the mu-receptor-deficient strain CxBk/ByJ mice were not affected. There was no difference in the response to morphine between male and female C3HeB/FeJ mice. Naltrexone reversed the morphine-induced suppression in the C3H strains, but not in C57Bl/6 mice. In addition, naltrexone caused significant mortality in Balb/cByJ mice. Spleen weight was decreased by morphine treatment in all the strains, but only the C3H strains were sensitive to the lethal effects of morphine. Thus, immune suppression did not correlate with splenic atrophy or mortality. The strain differences in response to chronic morphine and naltrexone treatment suggest that morphine may be acting through both opioid and non-classical opioid (e.g., not blocked by naltrexone) mechanisms.