Obesity and diabetes are serious health problems for Americans and especially for those with American Indian or Mexican ancestry. A preliminary survey by protein analysis rather than classical nucleic acid sequencing methods has suggested a correlation between a newly discovered T45S variant of apolipoprotein C1 (ApoC1), found only in persons with American Indian or Mexican ancestry, and elevated body mass index (BMI). American Indians with the S45 ApoC1 variant (n=36) had an average of 9% higher BMI than those who had only T45 ApoC1 (n=192, P=0.029). Elevated rates of diabetes were reported for parents of subjects with the S45 protein (P=0.006). In five gender-matched sibling pairs, persons with Mexican ancestry showed a 1.34-fold higher BMI for those with S45 ApoC1 (P=0.022). This protein may contribute to the elevated rates of diabetes in relevant ethnic groups and might be more common in isolated populations.