To compare the efficacy and tolerability of propionyl-1-carnitine with those of pentoxifylline in the treatment of intermittent claudication. This study was a phase II multicentre (n = 14), randomised, open trial. 114 patients were enrolled who had intermittent claudication [as diagnosed by an ankle/brachial pressure index (ABPI) ≤0.8 that decreased by ≥20% after exercise]. After a 6-week run-in phase, patients were randomised to 12 months of treatment with propionyl-L-carnitine (500mg orally, three times daily) or pentoxifylline (400mg orally, three times daily). Primary outcome measures included 12-month changes from baseline in claudication distance and maximal walking distance, as assessed by treadmill. Secondary outcome measures included ABPI and safety. Statistical analyses were performed in the per-protocol population (34 patients in each group). Compared with baseline, improvement in initial claudication distance was 174% with propionyl-L-carnitine versus 67% with pentoxifylline (p = 0.020). The improvement in maximal walking distance was 123 versus 54% (p = 0.004). There were no changes in electrocardiographic and routine biochemical and haematological tests that would indicate an adverse effect of either drug. Adverse events requiring drug discontinuation were five in the propionyl-L-carnitine group and eight in the pentoxifylline group. Resting and postexercise ABPI was not modified by treatments. The findings of this study suggest that propionyl-L-carnitine, a safe and well tolerated drug, is more effective than pentoxifylline in improving walking capacity in patients with intermittent claudication.