The immunotoxicity of the glycol ether 2-methoxyethanol (ME) was evaluated in adult Fischer 344 rats using a variety of in vitro and in vivo immune function assays. In the first phase of the study, male rats were dosed by oral gavage with ME in water, at dosages ranging from 50 to 200 mg/kg/day, for 10 consecutive days. In the second phase of the study, the PFC response to TNP-LPS was employed to assess the role that metabolism of ME to 2-methoxyacetic acid (MAA) plays in the immunotoxicity of this glycol ether. Ten-day oral dosing with MAA resulted in the inhibition of the PFC response to TNP-LPS at dosages of 50-200 mg/kg/day. Concomitant exposure of rats to ME and the alcohol dehydrogenase inhibitor 4-methylpyrazole blocked ME-induced suppression of this PFC response. Attempts to ameliorate ME-induced suppression of the PFC response with serine, which has been shown to reverse ME-induced developmental and reproductive toxicity, were unsuccessful. The results suggest that the immune system may be more sensitive than the reproductive system to the toxic effects of ME. Furthermore, it appears that MAA is the proximate toxicant for ME-induced alterations in the immune system as has been demonstrated for ME-induced reproductive and developmental toxicity.