Apolipoprotein E knockout (apoE-/-) mice fed a high-fat, Western-style diet for 6 months, are grossly hypercholesterolaemic and develop atherosclerotic lesions (1). In contrast to their male counterparts, female apoE-/- mice on high fat diet do not show evidence of occlusive coronary lesions or myocardial infarction (2). The aim of this work was to investigate whether high-fat diet is associated with increased apoptotic signalling (BCL2 and BAX protein expression) and whether gender is important. Female and male apoE-/- mice at 8 weeks old were either switched onto high fat, Western-type diet (21% fat; 0.15% cholesterol) or were maintained on normal rodent diet for approximately 6 months. Proteins were extracted from myocardial tissue collected from male (n=6) and female (n=6) mice. Half of the mice were fed high-fat diet. Western Blotting was used to estimate protein expression and data expressed as ratio to GAPDH (Chemicon Int.). Antibodies for BCL2 and BAX were purchased (Cell Signalling Technology) and used according to the suppliers instructions. Image J was used to estimate band intensity. Data are presented as mean±SE and differences determined using unpaired t-test (n=3 for each group). There was no difference in the ratio of BAX expression between male and female heart on normal diet (0.73±0.07 vs. 0.57±0.01). High-fat diet significantly decreased BAX expression in male heart (0.74±0.07 vs. 0.35±0.03, p<0.05) but causing an increase in female heart (0.57±0.01 to 0.99±0.08, p<0.05). BCL2 expression was higher in male compared to female heart on normal diet (0.84±0.13 vs. 0.23±0.14, p<0.05). High-fat diet decreased BCL2 expression in male heart (0.84±0.13 vs. 0.08±0.03, p<0.05) but increased the expression in female heart (0.23±0.14 to 0.89±0.09, p<0.05). This work indicates that high-fat diet and gender alter apoptotic signalling in hearts of apoE-/- mice. The changes appear to be associated with the incidence of coronary disease.