Myalgias and arthralgias are prominent toxicities associated with paclitaxel. Pursuant to pilot information suggesting that glutamine could markedly alleviate this toxicity, we developed a placebo-controlled, double-blind, randomized crossover trial to test this hypothesis. This trial studied 36 patients who had experienced myalgias/arthralgias related to a prior paclitaxel-containing regimen and who were then randomized to receive oral glutamine (10 grams three times a day, starting on the day of chemotherapy) x 5 days or an identical-appearing placebo. For the subsequent cycle of chemotherapy, patients were crossed over, again in a double-blind manner, to receive the alternative treatment. Patients recorded daily myalgia/arthralgia scores on numerical scales. Physicians recorded patient-reported myalgias/arthralgias using National Cancer Institute common toxicity criteria at baseline and after each course of therapy. The results of this study revealed that glutamine had no effect on the development or severity of paclitaxel-induced myalgias/arthralgias, as recorded either by the patients' daily logs or by physician-reported information. Glutamine was well tolerated, with no suggestion of more toxicity compared to placebo. Upon completion of the two cycles, patients were asked to indicate which of the two blinded courses they preferred. Of those patients indicating a preference, 29% preferred the glutamine cycle, compared with 33% who preferred the placebo cycle (P = 0.96). Thus this trial did not suggest any role for oral glutamine, compared with placebo, for preventing the development, or alleviating the severity, of paclitaxel-induced myalgias/arthralgias.