Background Acute CNS inflammatory demyelination in childhood may induce permanent cognitive impairment. However, there has been no epidemiological assessment of prognostic factors for school performance in a cohort of children with such a disease. Methods The cohort consisted of 344 children from the French “KIDSEP” neuropediatric cohort with at least one clinically defined attack of CNS inflammatory demyelination occurring before the age of 16 years, and with at least two years of follow-up (inclusion from 1990 to 2003, follow-up until June 2007). We used multivariate survival analysis (Cox model) to evaluate the prognostic value for grade retention between the start of elementary school (∼6 years of age) and the end of high school (∼17–18 years of age), of variables related to both the socioeconomic status of the parents and the characteristics of the disease at onset. Results The cohort was monitored for a mean of 8.0±3.4 years. Grade retention after disease onset was recorded for 151 patients (43.9%). The risk of grade retention was significantly higher for boys, children from families with lower social status and poorer housing conditions, children over the age of 11 years at disease onset and children suffering optic neuritis or brainstem dysfunction at the first attack or irreversible disability, even if only moderate, following the first attack. Conclusions The risk factors for poor school performance are related to low socioeconomic status and to factors predictive of a relapsing severe course of the disease, leading to the diagnosis of multiple sclerosis.