BACKGROUND: The neurobehavioral phenotype of 22q11.2 deletion syndrome (22q11DS) includes cognitive dysfunction and high rates of psychotic symptoms and schizophrenia. Existing research has mainly considered changes in IQ, especially its decline, as a psychosis predictor. The aim of this study was to investigate, in a longitudinal perspective, the relationship between neuropsychological abilities (not only IQ but also executive functioning, language and visual-motor integration abilities) and onset of psychotic symptoms in a sample of children, adolescents and young adults with 22q11DS. In addition, the role of comorbid psychiatric disorders at baseline was taken into account. METHODS: 75 participants with 22q11DS, aged between 6 and 27 years at baseline, were included. Eighteen of the 75 participants had developed psychosis at the one year follow-up (onset psychosis-OP) and constituted the first group; 57 participants who had not developed a psychosis at the one year follow-up (without onset psychosis-WOP) constituted the second group. RESULTS: At baseline, group OP showed lower IQ (both full scale and verbal and performance scale) and more perseverative errors as well as a reduced number of correct categories on the Wisconsin Card Sorting Test (WCST) compared to group WOP. In addition, at baseline, group OP showed a higher frequency of depressive disorders than group WOP. CONCLUSION: Even if with caution, results suggest neuropsychological deficits and depressive symptoms should be considered and monitored as possible clinical signs for the onset of psychosis in children, adolescents and young adults with 22q11DS.