Cortical spreading depression (CSD)-independent NMDA-evoked cortical blood flow (CoBF) increases in rats. Topical glutamate (10−3 M) and AMPA (10−4 M) administration prevented the NMDA (10−4 M)-induced CSD generation in 5 of 11 and 8 of 8 cases, respectively. Despite blocked CSD formation, coapplication of 10−4 M NMDA still resulted in a significant increase in CoBF, as compared with AMPA or glutamate application alone (expressed as average CoBF change of one minute at maximal rate of hyperemia). The CoBF increase was consistent with the post-CSD wave when only NMDA was applied (represented as the average increase of CoBF over a one-minute interval, three minutes after the peak, time-matched with CSD-independent CoBF increases). Data are mean±standard error of the mean; (n = 5–8; *P < 0.05) via one-way repeated measures analysis of variance and Tukey’s test.