While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% ± 5% (mean ± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation.