The aim of this study was to identify the high-risk factors associated with the development of ocular lesions in a large cohort of children with congenital toxoplasmosis (CT), irrespective of their gestational age at the time of maternal infection. Children were managed according to a standardized protocol and monitored for up to 14 years at the Croix-Rousse Hospital, Lyon, France. Cox model and a flexible regression, spline-based method were used for the analysis. During a median follow-up time of 6 years, 79 of the 327 children (24%) had at least one retinochoroidal lesion. No bilateral impairment of visual acuity was observed. The risk of a child developing ocular disease was higher not only when mothers were infected early during pregnancy, which was expected, but also when CT was diagnosed prior to or at the time of birth, when non-ocular manifestations were present at baseline and when birth was premature.