INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.