Nitrous oxide (N 2 O) and ketamine are common general anesthetics and antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors. In clinically relevant concentrations, they induce a psychotomimetic reaction in humans and pathomorphological changes in the rat brain. We have previously shown that ketamine and N 2 O in combination cause the neurotoxic reaction in young adult rat brain that is apparently synergistic. Ketamine and N 2 O are occasionally used in geriatric anesthesia since they do not suppress cardiorespiratory function and thus are beneficial for frail elderly patients. However, in view of the evidence that N 2 O and ketamine have potentially serious neurotoxic effects, and that they potentiate one another's neurotoxicity, their neurotoxic potential in the aging brain needs to be evaluated. In this study we compared the neurotoxicity of ketamine and N 2 O, alone or in combination, in aging (18- and 24-month-old) rats and in young adult (6-month-old) rats and found that the aging brain is substantially more sensitive than the young adult brain to the neurotoxic reaction induced by either ketamine alone or the ketamine + N 2 O combination, but equally sensitive to the neurotoxicity induced by N 2 O alone.