Anti-platelet agents such as aspirin and dipyridamole are main factors to prevent stroke in high-risk people. Pentoxyphiline has been reported as a red blood cell aggregation antagonist to prevent stroke. We evaluated the role of pento-xyphiline as an adjunct therapy to decrease risk of stroke in patients who were under treatment with aspirin or dipyridamole. A 5-years open labeled clinical trial was performed on 4465 patients with a history of thrombotic cerebrovascular accident. The patients divided into 2 groups. Group 1 (a total of 2230 patients, 1032 females and 1198 males) were under treatment by aspirin alone, and group 2 (a total of 2235 patients, 991 females and 1244 males) received aspirin + penthoxyphiline 400 mg/day. Subjects were followed prospectively for 5 years. The primary assessment was the proportion of patients who suffered another stroke. 193 patients in aspirin group and 213 patients out of the other group were excluded because of bleeding complication. After 5 years, 45.6% of the patients who received aspirin alone remained stroke-free as compared to 60.5% of those given aspirin + pentoxyphiline (P<0.007). In high risk patients for atherosclerotic stroke, combination treatment of aspirin and pentoxyphiline have better prognostic outcome.