The response of the brain to injury involves the accumulation of a large number of proliferating cells at the site of damage. Neither the identity nor the origin of these cells is unequivocally established. We have investigated this proliferative response after unilateral kainic acid lesions in the striatum of adult mice by labeling with tritiated thymidine (3H-thy) or bromodeoxyuridine (Brdu) to identify cells passing through S-phase. Labeled cells were seen only ipsilaterally in coronal section and extended laterally from the subependymal zone lining the lateral ventricle, through the striatal kainic acid injection site and into the cortex. The maximum proliferative response, after a single pulse of 3H-thy administered 4 h before sacrifice, was seen 6 days post-lesion close to the injection site. The proliferating cells were not astrocytes, as neither 3H-thy- nor Brdu-labeled cells were double-labeled with antisera to glial fibrillary acidic protein after the lesion. Animals given 3H-thy on day 3 post-lesion and then sacrificed on days 4, 5 or 6 post-lesion showed cumulative increases in the number of proliferating cells at the injection site with no increases in the surrounding tissue. We hypothesized that this reflected the presence of 2 sources of labeled cells: (1) an exogenous population of blood cells coming in through the broken blood-brain barrier and accumulating at the injection site and (2) endogenous cells (microglia) which are normally quiescent in the adult but proliferate in response to injury. By irradiating adult mice (900 rads) we attempted to selectively remove the blood stem cell precursors which gave rise to the proposed exogenous source of cells.(ABSTRACT TRUNCATED AT 250 WORDS)