National estimates of cancer mortality indicate relatively low rates for American Indians (AIs) and Alaska Natives (ANs). However, these rates are derived from state vital records in which racial misclassification is known to exist. In this cross-sectional study of cancer mortality among AIs and ANs living in counties on or near reservations, the authors used death records and census population estimates to calculate annualized, age-adjusted mortality rates for key cancer types for the period 1996-2001 for 5 geographic regions: East (E), Northern Plains (NP), Southwest (SW), Pacific Coast (PC), and Alaska (AK). Mortality rate ratios (MRRs) and 95% confidence intervals (95% CIs) also were calculated to compare rates with those in the general United States population (USG) for the same period. To examine temporal trends, MRRs for 1996-2001 were compared with MMRs for 1990-1995. The overall cancer mortality rate was lower in AIs and ANs (165.6 per 100,000 population; 95% CI, 161.7-169.5) than in the USG (200.9 per 100,000 population; 95% CI, 200.7-201.2). In the regional analysis, however, cancer mortality was higher in AK (MRR=1.26; 95% CI, 1.17-1.36) and in the NP (MMR=1.37; 95% CI, 1.31-1.44) than in the USG. In both regions, the excess mortality was attributed to cancer of the lung, colorectum, liver, stomach, and kidney. In the SW, the mortality rate for cancer of the liver and stomach was higher than the rate in the USG, in contrast with that region's nearly 4-fold lower mortality rate for lung cancer (MRR=0.23; 95% CI, 0.19-0.27). Rates of cervical cancer mortality were higher among AIs and ANs (MRR=1.35; 95% CI, 1.13-1.62), notably in the NP and SW. Rates of breast cancer mortality generally were lower (MRR=0.60; 95% CI, 0.55-0.66), notably in the PC, SW, and E. Cancer mortality increased by 5% in AIs and ANs (MRR for 1996-2001 compared with 1990-1995: 1.05; 95% CI, 1.01-1.08), whereas it decreased by 6% in the USG (MMR=0.94; 95% CI, 0.94-0.94). Regional data should guide local cancer prevention and control activities in AIs and ANs. The disparity in temporal trends in cancer mortality between AIs and ANs and the USG gives urgency to improving cancer control in this population.