We examined relations between brain volumes assessed by MRI and cognitive function in subjects in whom we have previously reported associations of cumulative lead dose with: (1) longitudinal declines in cognitive function; (2) smaller volumes of several regions of interest (ROIs) in the brain; and (3) increased prevalence and severity of white matter lesions. We used two complementary methods (ROI- [evaluating 20 ROIs] and voxel-wise) to examine associations between brain volumes and cognitive function using multiple linear regression. MRIs and cognitive testing were obtained from 532 former organolead workers with a mean (SD) age of 56.1 (7.7) years and a mean of 18.0 (11.0) years since the last occupational exposure to lead at the time of MRI acquisition. Cognitive testing was grouped into six domains of function (visuo-construction, verbal memory and learning, visual memory, executive functioning, eye-hand coordination, processing speed). Results indicated that larger ROI volumes were associated with better cognitive function in five of six cognitive domains, with significant associations observed for visuo-construction (15 of 20, p<or=0.05), processing speed (12, p<or=0.05), visual memory (11, p<or=0.05), executive functioning (11, p<or=0.05), and eye-hand coordination (11, p<or=0.05). Significant structure-function relations were also identified in the voxel-wise analysis with low false discovery rates (all less than 2.2%). Thus, larger volumes were associated with better cognitive function using both ROI- and voxel-based methods. In this cohort, an interesting group in which to examine structure-function relations, this finding provides a necessary condition to support the hypothesis that lead may influence cognitive function by its effect on brain volumes.