HIV-associated prospective memory (ProM) impairment has emerged, in earlier studies as a significant predictor of medication management and independence in activities of daily living. The relationship between ProM and white matter integrity in HIV has not previously been investigated. Participants, including 128 HIV-infected individuals and 32 healthy controls, were assessed using a comprehensive neuropsychological evaluation and both objective and subjective measures of ProM. Diffusion tensor imaging (DTI) was utilized to investigate the relationship of white matter integrity to ProM in a randomly selected subsample of 40 HIV positive subjects, using a whole brain voxel-based approach to define fractional anisotrophy (FA) and mean diffusion (MD). Total prospective memory was significantly poorer in the HIV positive group when compared with healthy controls (p = 0.023). Time-based ProM was poorer in the HIV group compared to healthy controls both without prompts (p = 0.001) and with prompts (p = 0.001). Poor Total ProM score correlated with performance on neuropsychological tests of executive functioning, information processing speed, learning, and working memory (p < 0.05). Those HIV positive participants with poor ProM had significantly decreased FA in the regions of superior corona radiata (p = 0.0035), the corpus collosum (p = 0.006) and the cingulum (p = 0.0033) when compared to those who were HIV positive with good ProM. This study reinforces the importance of ProM assessment in HIV.