Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and redox modulator. It has previously been reported to reduce infarct size in 7-day-old rat pups with an in vivo cerebral hypoxia/ischemia model (Jensen et al., 1994). In this study, we tested whether improvement is found in both behavioral measures of protection and by histological measures of infarcted tissue at 72 h after reversible middle cerebral artery occlusion (rMCAo) in adult rats. Two-hour rMCAo was induced in adult rats using the intraluminal suture technique. PQQ (10, 3, and 1 mg/kg) was given once by intravenous injection at the initiation, or 3 h after the initiation, of 2 h rMCAo. Neurobehavioral deficits were evaluated daily for 3 days followed by infarct volumes measurements by 2,3,5-triphenyltetrazolium chloride (TTC) staining. PQQ at 10 mg/kg infused at the initiation, or 3 h after the initiation, of rMCAo was effective in reducing cerebral infarct volumes measured 72 h later. At 3 h after ischemia, a dose of 3 mg/kg significantly reduced infarct volume compared to vehicle-treated animals, but 1 mg/kg was ineffective. Neurobehavioral scores were also significantly better in the PQQ-treated group compared to the vehicle controls when PQQ was given at 10 and 3 mg/kg, but not at 1 mg/kg. Thus, PQQ is neuroprotective when given as a single administration at least 3 h after initiation of rMCAo. These data indicate that PQQ may be a useful neuroprotectant in stroke therapy.