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Background: It was hypothesized that the use of Pentoxifylline would increase arterial O2 saturation and increase exercise tolerance in patients with Chronic Obstructive Pulmonary Disease (COPD). Methods: We tested this hypothesis in 23 patients with COPD and pulmonary hypertension. Patients were randomized to receive Pentoxifylline or placebo, each for a 12-week period, in a prospective, double-blind study to assess the effects of Pentoxifylline on oxygen saturation and exercise tolerance via pulse oximetry and the 6-Minute Walk Test (6MWT). Results: At the end of the 12 weeks, the six-minute walk distance rose from 351.9±65 meters to 393±67 meters in the Pentoxifylline group (10 patients) and increased from 328±79 meters to 353±66 meters in the placebo group (10 patients) (P=0.142). Resting oxygen saturation by pulse oximetry changed from 87±4% to 85±14% in the Pentoxifylline group and from 88±3% to 88±2% in the placebo group (P=0.676). There were no significant changes in dyspnea severity index and heart rate before and after the 6MWT. Conclusion: Pentoxifylline does not seem to improve exercise capacity and dyspnea in patients with severe and very severe COPD. Trial Registration Number: IRCT201202018889N1