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Carbon monoxide (CO) poisoning may result in focal and diffuse neuropathological changes, including basal ganglia lesions. The effect of CO poisoning on basal ganglia volumes over time is unclear. We assessed basal ganglia volumes longitudinally following CO poisoning. We prospectively enrolled 73 CO poisoned patients who underwent brain MR imaging on day 1 (baseline), 2 weeks, and 6 months post-CO poisoning. Basal ganglia volumes were obtained. One patient had bilateral globus pallidus lesions at two weeks and 6 months. Of the CO-poisoned patients 28% had volume reduction in at least one basal ganglia structure by 6 months, of which 21% had putamen, 15% had caudate, 15% had globus pallidus, and 16% had total basal ganglia volume reduction. Putamen volumes were significantly smaller from baseline to six months (p = 0.02). Verbal memory and mental processing speed correlated with smaller putamen and globus pallidus volumes. Carbon monoxide poisoning results in basal ganglia volume reduction 6 months post CO poisoning. Slow mental processing speed and impaired memory correlated with smaller putamen and globus pallidus volumes. Clinicians need to be aware of basal ganglia neuropathologic changes in the absence of observable lesions following CO poisoning.