Background: Lysophosphatidic acid (LPA) is a small phospholipid-signaling molecule, which can alter responses to stress in the central nervous system. Objective: We hypothesized that exogenous LPA would increase the size of infarct and reduce microregional O<sub>2</sub> supply/consumption balance after cerebral ischemia-reperfusion. Methods: This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with or without LPA (1 mg/kg, at 30, 60, and 90 min after reperfusion). Regional cerebral blood flow was determined using a C<sup>14</sup>-iodoantipyrine autoradiographic technique. Regional small-vessel (20–60 µm in diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. Results: There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic-reperfused cortex had a similar O<sub>2</sub> consumption to the contralateral cortex. However, microregional O<sub>2</sub> supply/consumption balance was significantly reduced in the ischemic-reperfused cortex with many areas of low O<sub>2</sub> saturation (43 of 80 veins with O<sub>2</sub> saturation below 50%). LPA did not significantly alter cerebral blood flow, but it did significantly increase O<sub>2</sub> extraction and consumption of the ischemic-reperfused region. It also significantly increased the number of small veins with low O<sub>2</sub> saturations in the reperfused region (76 of 80 veins with O<sub>2</sub> saturation below 50%). This was associated with a significantly increased cortical infarct size after LPA administration (11.4 ± 0.5% control vs. 16.4 ± 0.6% LPA). Conclusion: This suggests that LPA reduces cell survival and that it is associated with an increase in the number of small microregions with reduced local oxygen balance after cerebral ischemia-reperfusion.