PURPOSE: A recent report linked methylphenidate (MPH) use in children to cytologic abnormalities in plasma lymphocytes, a possible cancer biomarker. The purpose of this study was to investigate the association of MPH use and childhood cancer risk. METHODS: Using automated pharmacy databases and the SEER-affiliated cancer registry of the Kaiser Permanente Medical Care Program (KPMCP), we compared cancer rates at 18 sites among 35,400 MPH users who received it before age 20 to rates among KPMCP membership (age, sex, and calendar year standardized). Medical records of MPH exposed cancer cases were reviewed to identify the presence of established risk factors. RESULTS: There were 23 cancers among MPH users, versus 20.4 expected (standardized morbidity ratio, SMR = 1.13, 95% confidence interval (0.72, 1.70)). Given the small number of cancers, site-specific SMR estimates were imprecise. Only one SMR was statistically significant at the p < 0.05 level, which given the number of comparisons is consistent with the absence of a true association at any site. MPH use was associated with increased risk of lymphocytic leukemia (SMR = 2.64 (1.14, 5.20)), based on eight observed cases). The medical records of these exposed cases did not reveal any lymphocytic leukemia risk factors (prior cancer, radiotherapy or chemotherapy, or Down syndrome). CONCLUSIONS: Our results are consistent with no moderate or strong association between MPH use and cancer risk in children, although our ability to examine dose and duration of use or risk at specific sites was limited by small numbers. Further study of MPH use and lymphocytic leukemia risk is needed to determine whether our results are due to chance alone.