Background: Hand-foot syndrome (HFS)is a common side effect of capecitabine, although East Asian patients appear to have better tolerability. Methods: This study aimed to evaluate the incidence of grade ≥ 2 HFS in patients receiving pyridoxine versus placebo (primary objective), compare the time to onset of grade ≥ 2 HFS, and identify biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, plus genetic polymorphisms (secondary objectives). Patients starting capecitabine single-agent chemotherapy for breast, colorectal and other cancers in National Cancer Centre Singapore were randomized to receive concurrent pyridoxine (200mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by gender and use in adjuvant/neoadjuvant versus palliative setting. Patients were withdrawn from the study upon development of grade ≥ 2 HFS or cessation of capecitabine. Results: The trial was terminated before reaching the original target of 296 patients due to slow accrual. Grade ≥ 2 HFS occurred in 33 of 105 patients (31.4%, 95% CI: 22.6% - 40.3%) receiving pyridoxine compared to 39 of 103 patients (37.9%, 95% CI: 28.5% - 47.2%) receiving placebo (p = 0.329). The median starting dose of capecitabine was 1000mg/m² (range 793-1250 mg/m²) bid in the pyridoxine arm, and 1011mg/m² (range 845-1250 mg/m²) bid in the placebo arm (p = 0.667). The median time to onset of grade ≥ 2 HFS was not reached in patients on pyridoxine, compared to 174 days in patients on placebo (p = 0.677). On multivariate analysis, baseline serum folate (odds ratio 1.27 for every increase of 5nmol/l; 95% CI: 1.10-1.47; p = .001) was associated with increased risk of grade ≥ 2 HFS. Pyridoxine did not significantly decrease the risk compared to placebo (odds ratio 0.50; 95% CI: 0.24-1.03; p = 0.061). Initial dose intensity and baseline red cell folate were associated with increased risk of grade ≥ 2 HFS on univariate, not multivariate analysis. Genotyping with Zhonghua SNP arrays is in progress. Conclusions: Pyridoxine did not significantly prevent or delay the onset of grade ≥ 2 HFS. Serum folate was a significant predictor of HFS. Clinical trial information: NCT00486213