Although hydrocephalus rates have decreased with intrauterine surgery for myelomeningocele (MMC), 40%-85% of children with MMC still go on to develop hydrocephalus. Prenatal ventricle size is known to be associated with later development of hydrocephalus; however, it is not known how prediction measures or timing of hydrocephalus treatment differ between pre- and postnatal surgery for MMC. The goal of this study was to determine anatomical, clinical, and radiological characteristics that are associated with the need for and timing of hydrocephalus treatment in patients with MMC. The authors retrospectively identified patients from Barnes Jewish Hospital or St. Louis Children's Hospital between 2016 and 2021 who were diagnosed with MMC prenatally and underwent either pre- or postnatal repair. Imaging, clinical, and demographic data were examined longitudinally between treatment groups and hydrocephalus outcomes. Fifty-eight patients were included (27 females, 46.6%), with a mean gestational age at birth of 36.8 weeks. Twenty-three patients (39.7%) underwent prenatal surgery. For the overall cohort, the ventricle size at prenatal ultrasound (HR 1.175, 95% CI 1.071-1.290), frontal-occipital horn ratio (FOHR) at birth > 0.50 (HR 3.603, 95% CI 1.488-8.720), and mean rate of change in head circumference (HC) in the first 90 days after birth (> 0.10 cm/day: HR 12.973, 95% CI 4.262-39.486) were identified as predictors of hydrocephalus treatment. The factors associated with hydrocephalus in the prenatal cohort were FOHR at birth > 0.50 (HR 27.828, 95% CI 2.980-259.846) and the rate of change in HC (> 0.10 cm/day: HR 39.414, 95% CI 2.035-763.262). The factors associated with hydrocephalus in the postnatal cohort were prenatal ventricle size (HR 1.126, 95% CI 1.017-1.246) and the mean rate of change in HC (> 0.10 cm/day: HR 24.202, 95% CI 5.119-114.431). FOHR (r = -0.499, p = 0.008) and birth HC (-0.409, p = 0.028) were correlated with time to hydrocephalus across both cohorts. For patients who underwent treatment for hydrocephalus, those in the prenatal surgery group were significantly more likely to develop hydrocephalus after 3 months than those treated with postnatal surgery, although the overall rate of hydrocephalus was significantly higher in the postnatal surgery group (p = 0.018). Clinical and imaging factors associated with hydrocephalus treatment differ between those receiving pre- versus postnatal MMC repair, and while the overall rate of hydrocephalus is lower, those undergoing prenatal repair are more likely to develop hydrocephalus after 3 months of age. This has implications for clinical follow-up timing for patients treated prenatally, who may live at a distance from the treatment site.