Rationale. Individuals prenatally exposed to alcohol often have impaired working memory. Neuropsychological studies have further suggested that spatial working memory (SWM) may be significantly affected in this group. Studies of the neural correlates of working memory have consistently shown the involvement of a fronto-parietal network. Despite evidence for microstructural and functional abnormalities in frontal and parietal regions in individuals prenatally exposed to alcohol, the relation and contribution of these abnormalities to SWM deficits remain unclear. The main goal of this study was to expand on previous research by using a multimodal imaging approach to examine brain structure and function associated with SWM deficits in children prenatally exposed to alcohol. Design. Children ages 10 to 16 with histories of heavy prenatal alcohol exposure (AE group; n = 18) and non-exposed controls (CON group; n = 19) underwent functional magnetic resonance imaging while performing a SWM task and diffusion tensor imaging. Whole-brain blood oxygen level dependent (BOLD) response to SWM relative to vigilance trials (SWM — vigilance contrast) was computed for each participant. Whole brain task-related functional connectivity of bilateral dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC) seed regions were estimated for each participant using a psychophysiological interaction approach. Fractional anisotropy and mean diffusivity were used as indices of white matter integrity. Independent samples ttests were used to examine group differences in BOLD response contrast, task-based functional connectivity, and white matter integrity of the superior longitudinal fasciculus (SLF) and genu of the corpus callosum (GCC). Results. Children in the AE group were less accurate than children in the CON group when performing the SWM task (p = .008). Group differences in neural activity to the SWM — vigilance contrast were found primarily in frontal, parietal, and cingulate regions. In all regions, the CON group showed greater BOLD response contrast compared to the AE group. Results from the functional connectivity analyses revealed positive coupling between bilateral DLPFC seeds and regions within the fronto-parietal network in the CON group, whereas the AE group showed negative connectivity. In contrast to the CON group, the AE group showed positive connectivity between PPC seeds and frontal lobe regions. Across seeds, weaker negative coupling with regions outside the fronto-parietal network (e.g., left middle occipital gyrus) were observed in the AE group relative to the CON group. Functional data clusters were considered significant at p < .05 (with an uncorrected voxelwise threshold: p < .05; minimum cluster volume: 63 voxels). No significant groups differences were noted with respect to white matter integrity in the SLF and GCC. Conclusions. Overall findings suggest that localized alterations in neural activity, aberrant fronto-parietal network synchrony, and poor coordination of neural responses with regions outside of this network may help explain SWM deficits in individuals with a history of heavy prenatal alcohol exposure. Greater understanding of the neural mechanism underlying cognitive deficits in children prenatally exposed to alcohol may contribute to the development of targeted interventions, and may serve as a potential neurobiological marker of treatment outcomes.