Aim:  The aim of the present study was to compare the efficacy of 200 mg versus 400 mg daily of pyridoxine in preventing or delaying the onset of palmar-plantar erythrodysesthesia (PPE) in capecitabine-treated patients.Methods:  Patients with histologically confirmed breast cancer or colorectal cancer receiving single agent capecitabine started at 2000 to 2500 mg/m2 daily from day 1 to 14 every 3 weeks were randomly assigned to receive 200 mg or 400 mg daily of pyridoxine for PPE prophylaxis. The primary endpoint was the reduction of incidence of grade 2 or greater PPE. Secondary endpoints were reduction of severe PPE and prolongation of time to development of grade 2 or greater PPE.Results:  There were 56 patients in this study. The baseline characteristics were generally similar in both groups. The high dose arm had less PPE than the low dose arm (11 of 28 or 39% vs 20 of 28 or 71%, relative risk = 0.26 [0.08, 0.79], P = 0.031). Grade III PPE developed in 3 of 28 (10.7%) versus none in patients receiving 200 mg versus 400 mg pyridoxine, respectively (relative risk 2.12 [1.594, 2.819], P = 0.24). High dose pyridoxine had a longer time to development of grade 2 or greater PPE compared to the low dose arm, 87 days versus 62 days. The 400 mg pyridoxine group had, however, a worsened tumor response and tended to have greater tumor treatment failure and shorter time to treatment failure. Conclusion:  With the limitation of sample size in this study, there was a trend to improve PPE incidence and time to event with a higher dose of pyridoxine. Further validation of these results in a larger population is warranted.