Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and -cell dysfunction. Islet amyloid is associated with reduced -cell mass and function and develops in the majority of our C57BL/6JxDBA/2J (F1) male human islet amyloid polypeptide (hIAPP) transgenic mice after one year of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n=13; and DBA2 n=11) and C57BL/6JxDBA/2J F1 mice (n=17) on a 9% (w/w) fat diet for one year. At the end of 12 months, islet amyloid deposition was quantified from thioflavin S stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F1: 76%, DBA2: 100%). However, the prevalence (% amyloid positive islets; BL6: 14±3%, F1: 44±8%, DBA2: 49±9%, p<0.05) and severity (% islet area occupied by amyloid; BL6: 0.03±0.01%, F1: 9.2±2.9%, DBA2: 5.7±2.3%, p0.01) were significantly lower in BL6 than F1 and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin positive area per islet, in F1 (r²=0.75, p<0.001) and DBA2 mice (r²=0.87, p<0.001) but not BL6 mice (r²=0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F1 and DBA2 mice) being more susceptible to amyloid deposition that replaces -cell mass. These findings underscore the importance of genetic as well as environmental factors in studying metabolic disease.