OBJECTIVE: To investigate the therapeutic effect of DL-3- n-butylphthalide (DL-NBP) in rats with chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was modelled by bilateral permanent occlusion of common carotid arteries in Wistar rats. The therapeutic effect of DL-NBP in hypoperfused rats was evaluated using the Morris water maze task. The levels and deposition of matrix metalloproteinase (MMP) and the amyloid precursor protein β-amyloid 40 (Aβ40) were measured by Western blot analysis and immunohistochemistry in the cerebral cortex and hippocampus. RESULTS: Treatment with DL-NBP significantly improved the learning and memory ability of hypoperfused rats. Western blot analysis indicated that, in comparison with the sham-operated control group, protein levels of Aβ40 and MMP-2 were significantly increased in the cerebral cortex of hypoperfused rats, and treatment with DL-NBP prevented this hypoperfusion-induced increase in Aβ40 and MMP-2. Immunohistochemical analysis showed that Aβ40 and MMP-2 were deposited in venous endothelial cells at day 3 and in arterial endothelial cells at day 14 after hypoperfusion. CONCLUSION: This study indicated that DL-NBP has therapeutic effects on chronic cerebral hypoperfusion and provided a useful insight into the potential molecular mechanisms underlying the therapeutic effect of DL-NBP in chronic cerebral hypoperfusion.