BACKGROUND Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. METHODS A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. RESULTS Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10-7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10-5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10-6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10-4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10-5 ). CONCLUSIONS These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society.