Cigarette smoking is the leading preventable cause of death worldwide. American Indians have the highest proportion of smoking in the United States. However, few studies have examined the impact of cigarette smoking on disease mortality in this ethnically important but traditionally understudied minority population. Here we estimated the association of cigarette smoking with cardiovascular disease (CVD), cancer and all-cause mortality in American Indians participating in the Strong Heart Study, a large community-based prospective cohort study comprising of 4549 American Indians (aged 45-74 years) followed for about 20 years (1989-2008). Hazard ratio and population attributable risk (PAR) associated with cigarette smoking were estimated by Cox proportional hazard model, adjusting for sex, study site, age, educational level, alcohol consumption, physical activity, BMI, lipids, renal function, hypertension or diabetes status at baseline, and interaction between current smoker and study site. We found that current smoking was significantly associated with cancer mortality (HR 5.0, [1.9-13.4]) in men, (HR 3.9 [1.6-9.7] in women) and all-cause mortality (HR 1.8, [1.2-2.6] in men, HR 1.6, [1.1-2.4] in women). PAR for cancer and all-cause mortality in men were 41.0 and 18.4 %, respectively, whereas the corresponding numbers in women were 24.9 and 10.9 %, respectively. Current smoking also significantly increases the risk of CVD deaths in women (HR 2.2 [1.1, 4.4]), but not men (HR 1.2 [0.6-2.4]). PAR for CVD mortality in women was 14.9 %. In summary, current smoking significantly increases the risk of CVD (in women), cancer and all-cause mortality in American Indians, independent of known risk factors. Culturally specific smoking cessation programs are urgently needed to reduce smoking-related premature deaths.