OBJECTIVE: Heredity has long been known as a risk factor for non-insulindependent diabetes mellitus (NIDDM), but the mode of inheritance of NIDDM remains unclear. We examined the distribution of diabetes in 29 Mexican-American families ascertained on a diabetic proband. RESEARCH DESIGN AND METHODS: Probands represented a random sample of diabetic Mexican Americans residing in low-income neighborhoods from San Antonio, TX. A total of 375 family members of these diabetic probands were examined, and diabetes was diagnosed according to the World Health Organization lasma glucose criteria. RESULTS: The prevalence of diabetes decreased from 28.2% in first-degree relatives of the probands to 13.3% in second-degree relatives to 11.1% in third-degree relatives. When compared with Mexican Americans with no parental history of diabetes, this represents an excess of diabetes of 2.0-, 1.3-, and 1.1-fold in first-, second-, and thirddegree relatives, respectively. Five of the 29 probands (17%) had an age of diabetes onset <40 years. In the first-degree relatives of these early-onset probands, diabetes prevalence was 47.0% (16 of 34) compared with only 24.1% (34 of 141) in the first-degree relatives of the 24 late-onset probands. After adjustment for age, this excess represented a fivefold increase in the odds of diabetes among relatives of the early-onset probands compared with relatives of the late-onset probands (P < 0.001). Moreover, the 16 affected family member of the early-onset probands had a mean age of diabetes onset of 42.7 years compared with 49.9 years for the 34 affected members of the late-onset probands, although this difference was not statistically significant (P = 0.13). CONCLUSIONS: NIDDM may be genetically heterogeneous in this Mexican- American population, with family members of early-onset diabetes patients being at higher risk for NIDDM than family members of late-onset diabetes patients.