Background-National vital event data suggest that cardiovascular disease (CVD) mortality rates are lower for American Indians and Alaska Natives (AIAN) than for the general US population, but these data are disproportionately flawed for AIAN because of racial misclassification. Methods and Results-Vital event data adjusted for racial misclassification and published by the Indian Health Service were used to compare trends in CVD mortality from 1989 to 1991 to 1996 to 1998 between AIAN, US all-races, and US white populations. Without misclassification accounted for, AIAN initially had the lowest mortality rates from major CVD, but by the end of the study, their rates were the highest. Adjustment for misclassification revealed an early and rapidly growing disparity between CVD mortality rates among AIAN compared with rates in the US all-races and white populations. By 1996 to 1998, the age-and misclassification-adjusted number of CVD deaths per 100 000 among AIAN was 195.9 compared with age-adjusted rates of 166.1 and 159.1 for US all races and whites, respectively. The annual percent change in CVD mortality for AIAN was 0.5 compared with Ϫ1.8 in the other groups. Regardless of racial misclassification, the most striking and widening disparities were found for middle-aged AIAN, but CVD mortality among AIAN Ն65 years of age was lower than in the other populations. Conclusions-A previously underrecognized disparity in CVD mortality exists for AIAN, particularly among middle-aged adults. Moreover, these disparities are increasing. Efforts to reduce CVD mortality in AIAN must begin before the onset of middle age.