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Low-molecular-weight acid phosphatase (ACP1) is a poly-morphic protein-tyrosine phosphatase present in all human tissues, including adipocytes. A positive association between the low-activity ACP1*A/*A genotype and extreme body mass index has previously been shown by us in obese subjects from the population of Rome. We have now studied a sample of 265 subjects with non-insulin-dependent diabetes mellitus (niddm) from another Italian population. There is a significant interaction between ACP1, body mass index, and blood lipid level. A highly significant positive association between ACP1*A/*A and high body mass index similar to that previously observed in obese sub- jects from the population of Rome is present only in those niddm subjects with blood lipid levels within the normal range. In NIDDM subjects the low-activity ACP1*A/*A variant seems to favor the increase of body mass or blood lipid levels or both. The pattern of association is independent of sex, age at survey, age at onset of diabetes, duration of disease, and therapy.