This study evaluated the effect of possible synergic interaction between high fat diet (HF) and hydrochlorothiazide (HCTZ) on biochemical parameters of oxidative stress in brain. Rats were fed for 16 weeks with a control diet or with an HF, both supplemented with different doses of HCTZ (0.4, 1.0, and 4.0 g kg(-1) of diet). HF associated with HCTZ caused a significant increase in lipid peroxidation and blood glucose levels. In addition, HF ingestion was associated with an increase in cerebral lipid peroxidation, vitamin C and non-protein thiol groups (NPSH) levels. There was an increase in vitamin C as well as NPSH levels in HCTZ (1.0 and 4.0 g kg(-1) of diet) and HF plus HCTZ groups. Na(+)-K(+)-ATPase activity of HCTZ (4.0 g kg(-1) of diet) and HCTZ plus HF-fed animals was significantly inhibited. Our data indicate that chronic intake of a high dose of HCTZ (4 g kg(-1) of diet) or HF change biochemical indexes of oxidative stress in rat brain. Furthermore, high-fat diets consumption and HCTZ treatment have interactive effects on brain, showing that a long-term intake of high-fat diets can aggravate the toxicity of HCTZ.