Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 μg g-1 creatinine (geometric mean = 0.94 μg g-1) and it was correlated with smoking pack-year among ever-smokers (r2 = 0.16, P < 0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 μg g-1 creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (β) = 1.64, P = 0.002). These associations were present among light- and never-smokers (β = 2.03, P = 0.002, n = 2627), although not significant among never-smokers (β = 1.22, P = 0.18, n = 1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (β = 0.94, P = 0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.