The development of natural killer (NK) cell activity was assessed in Fischer 344 (F344) rats sympathectomized as neonates with the neurotoxin, 6-hydroxydopamine (6-OHDA). No NK cell activity was detected in sympathectomized or vehicle-injected control animals at 7 days of age. At 10 and 14 days of age, NK cell activity was reduced in spleens from sympathectomized male and female rats. At 21 days of age, a reduction in NK cell activity was detected only in sympathectomized male rats. Sympathectomy did not alter NK cell activity at 28 and 42 days of age in either gender. At 56 days of age, NK cell activity was increased in neonatally sympathectomized females; rats of both genders acutely sympathectomized at 56 days of age also showed enhanced NK cell activity. No differences were observed at 90 days of age in neonatally or acutely sympathectomized males of females. Prior treatment with desipramine, which blocks uptake of 6-OHDA into nerve terminals and prevents the destruction of sympathetic nerve terminals, prevented these 6-OHDA-induced effects, suggesting that sympathectomy, and not direct toxic effects of 6-OHDA treatment of NK cells, accounted for the alterations in NK cell activity. Together, these results indicate that the sympathetic nervous system is an integral component of the developing lymphoid and hematopoietic microenvironment.