Purpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1-4), providing 198 data points for analysis. Results: Participants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed. Conclusions: Noncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills.