The effect of morphine administration on immune parameters is well documented. However, there exists a limited knowledge of the effect of morphine's metabolites on immune status. The present study examines the immunomodulatory effects of the morphine metabolite, morphine-6β-glucuronide (M6G), in the rat and provides further evaluation of the antinociceptive effects of M6G. Animals were administered phosphate-buffered saline (PBS) or M6G in doses of 1.0, 3.16, or 10.0 mg/kg (subcutaneous (s.c.)) or 0.1, 0.316, or 1.0 μg (intracerebroventricular (i.c.v.)). Animals were tested for antinociception in the warm water tail-withdrawal procedure. In a separate set of animals, assessments of splenic natural killer cell activity, lymphocyte proliferative responses to mitogenic stimulation, and production of interferon-γ were made 1 h following the s.c. or i.c.v. administration of M6G. The results show that M6G induced potent antinociception that was evident for at least 120 min following administration. M6G also produced decreases in natural killer cell activity, lymphocyte proliferation, and interferon-γ production 1 h following both routes of administration. The difference in potency between immune alterations induced by subcutaneous vs. intracerebroventricular administration suggest central mediation of the immunomodulatory properties of M6G. Thus, M6G produces significant antinociception and immunomodulation in the rat. These findings demonstrate potent immunomodulatory properties of a metabolite of morphine, M6G.