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BACKGROUND We assessed the effects of lopinavir/ritonavir on neurobehaviour, neurochemistry and oxidative status in healthy mice. Also, the impact of high dietary fat on the parameters measured was also assessed. METHODS Mice were randomly-assigned into eight groups of ten (n=10) animals each. The groups were normal control (standard diet), high-fat control (high-fat diet), 3 groups of lopinavir/ritonavir incorporated into standard diet (100/25, 200/50 and 400/100 mg/kg of feed), and 3 groups of lopinavir/ritonavir incorporated into high fat diet (100/25, 200/50 and 400/100 mg/kg of feed). Mice were fed ad libitum for six weeks, and then behaviours in the open field, elevated-plus maze (EPM), radial-arm maze and Y-maze were scored. Twenty-four hours after the last behavioural test, mice in all groups were euthanised. Brain was homogenised for estimation of oxidative stress parameters, L-glutamate level and acetylcholinesterase activity. RESULTS Incorporation of lopinavir/ritonavir with high-fat diet was associated with a reduction in high-fat diet-induced weight gain without significant effect on food intake. High fat diet reversed the decrease in open-field novelty-induced behaviours, spatial working memory scores and anxiolytic response that was associated with administration of lopinavir/ritonavir in food. Dietary composition did not significantly alter lopinavir/ritonavir's effects on oxidative status, L-glutamate and brain acetylcholinesterase activity. CONCLUSION In conclusion, the study shows that while dietary composition may alter the neurobehavioural responses to lopinavir/ritonavir in healthy mice, its effects on oxidative status, L-glutamate and acetylcholinesterase activity remains relatively unaffected.