Pyrroloquinoline quinone (PQQ) is a redox active essential nutrient that can generate or scavenge superoxide depending on its microenvironment. PQQ has been shown previously to be neuroprotective in a rodent stroke model. Here we test whether PQQ interacts with reactive nitrogen species, known to be involved in the pathogenesis of stroke. Using rat forebrain neurons in culture, we determined that the toxicity of SIN-1 was mediated by peroxynitrite and that PQQ could block this toxic action. However, PQQ could not block the toxicity of peroxynitrite itself. Both SIN-1 and peroxynitrite caused ATP depletion, but only SIN-1 evoked ATP depletion was blocked by PQQ. In a cell-free system, PQQ blocked nitration of bovine serum albumin produced by SIN-1, but potentiated peroxynitrite-induced nitration. PQQ was unable to block ATP depletion and cell death induced by NO· donors (DEA/NO, DPT/NO and DETA/NO), indicating that it does not directly interact with nitric oxide, and suggesting that it acts as a superoxide scavenger. PQQ significantly potentiated cGMP accumulation evoked by SIN-1, similar to the effect of superoxide dismutase (SOD). However, unlike SOD, which potentiated neurotoxicity induced by SIN-1, PQQ blocked its toxicity, arguing against the possibility that PQQ functions simply as a SOD mimetic. Indeed, substantially less H2O2 was produced by the incubation of SIN-1 with PQQ, when compared to SOD. These results suggest that PQQ scavenges superoxide without forming toxic levels of H2O2. Therefore, the protective effect of PQQ on stroke might be due, at least in part, to the suppression of peroxynitrite formation.