Objective To study the preventive effects of single use of azathioprine and its combination with methylprednisolone on chronic cerebral vasospasm (CVS). Methods A canine model of the "double subarachnoid hemorrhage(SAH)" was established to study the angiogram characteristics of chronic CVS. The effects of azathioprine and its combination with methylprednisolone on the prevention of chronic CVS were observed in a randomized study. The content of malondialdehyde (MDA) and pathological changes in the basilar artery (BA) wall were also analyzed. Results The results were obtained on the 7th day after subcarachnoid hemorrhage. In the azathioprine group, the BA diameter was 87% +/- 26% Of the original BA diameter, and the MDA content of BA wall was 0.03 +/- 0.01 nmol/mg tissue. In the azathioprine plus methylprednisolone group, it was 93% +/- 20% (BA diameter) and 0.02 +/- 0.01 nmol/mg tissue (MDA content). In the control group, the BA diameter was 53% +/- 19% and MDA content was 0.11 +/- 0.05 nmol/mg tissue. Pathological examination confirmed the reduction in BA wall damage in the experimental groups. Conclusion Azathioprine has a preventive effect on chronic CVS following SAH. It may suppress the production of free radicals and reduce damage to the BA wall. Combined use of azathioprine with methylprednisolone allows lower dosage and less complication compared with a single agent, and results in a better outcome.