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Background: Latinos are the largest minority group in the United States. We assessed cancer mortality by birthplace and generation status of Mexican Latinos in the Multiethnic Cohort., Methods: We included 26 751 Latinos of Mexican origin and 6093 non-Latino Whites aged 45-74 years at cohort entry (1993-1996) from the California Multiethnic Cohort component. The Mexican Latinos comprised 42% first-generation Mexico-born immigrants, 42% second-generation (28% US-born with both parents Mexico-born and 14% US-born with 1 parent US-born and 1 parent Mexico-born), and 16% third-generation or more who were US-born with both parents US-born. Multivariable Cox models were used to calculate covariate adjusted hazard ratios and 95% confidence intervals for overall and site-specific cancer mortality by birthplace and generation status. All statistical tests were 2-sided., Results: Cancer death rate was highest among the US-born with 1 parent US-born and 1 parent Mexico-born (age-adjusted rate = 471.0 per 100 000 person-years) and US-born with both parents US-born (age-adjusted rate = 469.0 per 100 000 person-years) groups. The US-born with both parents Mexico-born group had a 30% (hazard ratio = 1.30, 95% confidence interval = 1.18 to 1.44) higher risk of cancer death than the first-generation Mexico-born immigrants group, showing US birthplace was associated with an elevated cancer mortality. For cancer-specific mortality, US birthplace was positively associated with colorectal, liver and lung, and ovarian cancer (P values ranged from .04 to .005). Among US-born Mexican Latinos, generation status was not statistically significantly associated with overall cancer or site-specific cancer mortality., Conclusions: Our findings suggest that US birthplace is a risk factor for cancer death in Mexican Americans. Identification of the contributing factors is important to curtail patterns of increasing cancer mortality in US-born Mexican Latinos., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)