In this double-blind trial in 60 recreational athletes suffering from Achilles peritendinitis, we compared the effect of local injections of glycosaminoglycan polysulfate (GAGPS) with oral indomethacin (IM) administered over a 2-week period. Orthotic devices were prescribed in 66% of the cases to control biomechanical errors. The results after 1-year follow-up showed that GAGPS had a good overall therapeutic effect on two-thirds of the patients compared to one-third of the IM treated. In the patients with symptoms lasting longer than 3 months, IM had an effect in only 12% while GAGPS was beneficial in 59%. Twenty-five cases of non-responders and relapses underwent a crossover treatment. Those who received IM in this second period did not benefit from this treatment while those who received GAGPS showed a moderate to good effect in 8/17 (47%) after a 2-week follow-up. A different mode of action is suggested as an explanation of the encouraging results.