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Background Inorganic arsenic at high and prolonged doses is highly neurotoxic. Few studies have evaluated whether long-term, low-level arsenic exposure is associated with neuropsychological functioning in adults. Objectives To investigate the association between long-term, low-level inorganic arsenic exposure and neuropsychological functioning among American Indians aged 64–95. Methods We assessed 928 participants in the Strong Heart Study by using data on arsenic species in urine samples collected at baseline (1989–1991) and results of standardized tests of global cognition, executive functioning, verbal learning and memory, fine motor functioning, and speed of mental processing administered during comprehensive follow-up evaluations in 2009–2013. We calculated the difference in neuropsychological functioning for a 10% increase in urinary arsenic with adjustment for sex, age, education, and study site. Results The sum of inorganic and methylated arsenic species (∑As) in urine was associated with limited fine motor functioning and processing speed. A 10% increase in ∑As was associated with a .10 (95% CI −.20, −.01) decrease on the Finger Tapping Test for the dominant hand and a .13 decrease (95% CI −.21, −.04) for the non-dominant hand. Similarly, a 10% increase in ∑As was associated with a .15 (95% CI −.29, .00) decrease on the Wechsler Adult Intelligence Scale–Fourth Edition Coding Subtest. ∑As was not associated with other neuropsychological functions. Conclusions Findings indicate an adverse association between increased urinary arsenic fine motor functioning and processing speed, but not with other neuropsychological functioning, among elderly American Indians. [ABSTRACT FROM AUTHOR]