The neurochemical and endocrine responses to inoculation of mice with the murine lymphoma cell line AW5E was studied. This cell line was chosen because it is NK cell lysis resistant and thus does not induce a normal immune response. Immune activation has long been known to be a potent stimulator of the hypothalamo-pituitary-adrenocortical (HPA) axis as well as brain catecholamine and indoleamine metabolism, involving increases in the brain concentrations of catabolites of norepinephrine (NE) and serotonin (5-HT), as well as free tryptophan. Mice injected intravenously with AW5E tumor cells exhibited small increases in plasma corticosterone and hypothalamic NE and 5-HT catabolites one day after injection. There were no significant changes after 6 or 8 days, but a sustained increase in hypothalamic NE and 5-HT metabolism appeared 10 days after injection. There were similar, but more limited changes in the brain stem and prefrontal cortex. On the last day tested (day 14), plasma corticosterone was slightly elevated, as were hypothalamic dopamine, NE and 5-HT catabolites and tryptophan. These results indicate that inoculation with AW5E tumor cells increases brain catecholamine and serotonin metabolism, the hypothalamus being the most sensitive region. The most marked increases occurred in the few days preceding death, and thus may be associated with the pathology of the tumor growth.