Although the Picture Exchange Communication System (PECS) has been demonstrated to be an effective intervention to teach people diagnosed with autism spectrum disorder a functional communication system, the research indicates variability in PECS outcomes across people and studies. Therefore, the purpose of the current study was to explore child characteristics and treatment variables that may explain the variation in, and potentially predict, PECS outcomes. A total of 22 children and youth diagnosed with autism or a related developmental disorder, all of whom scored substantially below average on standardized measures of cognitive and adaptive abilities, participated in a PECS intervention. Participants who achieved high phases of PECS (≥PECS phase IIIb) differed significantly from those who mastered lower PECS phases (≤PECS phase IIIa) in terms of overall, verbal, and nonverbal mental age, matching abilities, and adaptive behavior level. Stimulus generalization was also associated with significant variation in PECS outcome. PECS outcomes could be predicted with good accuracy using a combination of these child characteristics and treatment variables. The findings from the current study suggest that children with relatively higher cognitive and adaptive skill levels are more likely to achieve higher phases of PECS; further, approaches to generalization training also play a role. Factors such as autism symptom severity and parental ratings of maladaptive behavior were not associated with significant differences in PECS outcomes. However, more research is needed. Gaining a better understanding of predictors of PECS outcomes is important to inform intervention, provide more accurate outcome expectations for families, and guide PECS teaching procedures. Although participants were more likely to achieve higher phases of PECS if they had a higher mental age, adaptive skill level, and matching skills, the average scores for these measures were well below those expected for same age peers. These results indicate that PECS is appropriate for use with children with clinically significant deficits in cognitive and/or adaptive abilities. Further, results suggest that even children who demonstrate more severe symptoms of autism and exhibit more challenging behavior can achieve higher phases of PECS.