Systemic nitric oxide synthase inhibition (NOSI) decreases cerebral blood flow, which may worsen ischemic insults. To examine the local effects of NOSI without this confounding effect, we examined the role of a locally administered NOSI, N(G)-nitro-L-argininemethyl-ester (L-NAME), on neurotransmitter recovery during cerebral ischemia. Rats were assigned to one of three groups: locally administered L-NAME via a striatal microdialysis probe (n = 11), systemic L-N AME (n = 5), or control (n = 11). Temporary global forebrain ischemia was induced for 15 min, followed by 60 min of reperfusion, L-NAME resulted in decreases of basal aspartate (ASP; 74% of basal) and glutamate (GLU; 60% of basal) recovery. While systemic L-NAME caused significant increases in ischemic ASP and GLU recovery (by 224% and 110%, respectively, compared with ischemic controls), local NOSI administration resulted in a significant attenuation of peak ASP, GLU, glycine, and γ-aminobutyric acid recovery (43%, 38%, 53%, and 72%, respectively, compared with ischemic controls). We conclude that local NOSI attenuated ischemic neurotransmitter recovery during ischemia/reperfusion. Our results emphasize the importance of the systemic effects of NOSI and suggest both deleterious and beneficial effects of NOSI during ischemia/reperfusion.