Background  The primary objective of the current study was to examine the childhood predictors of adolescent reading comprehension in velo‐cardio‐facial syndrome (VCFS). Although much research has focused on mathematics skills among individuals with VCFS, no studies have examined predictors of reading comprehension. Methods  69 late adolescents with VCFS, 23 siblings of youth with VCFS and 30 community controls participated in a longitudinal research project and had repeat neuropsychological test batteries and psychiatric evaluations every 3 years. The Wechsler Individual Achievement Test – 2nd edition (WIAT‐II) Reading Comprehension subtest served as our primary outcome variable. Results  Consistent with previous research, children and adolescents with VCFS had mean reading comprehension scores on the WIAT‐II, that were approximately two standard deviations below the mean and word reading scores approximately one standard deviation below the mean. A more novel finding is that relative to both control groups, individuals with VCFS demonstrated a longitudinal decline in reading comprehension abilities yet a slight increase in word reading abilities. In the combined control sample, WISC‐III FSIQ, WIAT‐II Word Reading, WISC‐III Vocabulary and CVLT‐C List A Trial 1 accounted for 75% of the variance in Time 3 WIAT‐II Reading Comprehension scores. In the VCFS sample, WISC‐III FSIQ, BASC‐Teacher Aggression, CVLT‐C Intrusions, Tower of London, Visual Span Backwards, WCST Non‐perseverative Errors, WIAT‐II Word Reading and WISC‐III Freedom from Distractibility index accounted for 85% of the variance in Time 3 WIAT‐II Reading Comprehension scores. A principal component analysis with promax rotation computed on the statistically significant Time 1 predictor variables in the VCFS sample resulted in three factors: Word reading decoding/Interference control, Self‐Control/Self‐Monitoring and Working Memory. Conclusions  Childhood predictors of late adolescent reading comprehension in VCFS differ in some meaningful ways from predictors in the non‐VCFS population. These results offer some guidance for how best to consider intervention efforts to improve reading comprehension in the VCFS population.