Objective Schizophrenia is associated with neurocognitive deficits, but its etiologic heterogeneity may complicate the delineation of a neurocognitive profile. Schizophrenia associated with 22q11 Deletion Syndrome (22qDS) represents a more genetically homogeneous subtype for study. We hypothesized that in adults with 22qDS the neurocognitive profiles would differ between those with and without schizophrenia. Method Using a comprehensive battery of tests, we compared the neurocognitive performance profiles in those with schizophrenia (n =27; 14 M, 13 F; mean age=30.6 years, SD=7.7 years) and those with no history of psychosis (n =29; 16 M, 13 F; mean age=25.0 years, SD=9.0 years). Results The 22qDS groups with and without schizophrenia had similar mean estimated IQ (71.6, SD=8.2 and 74.8, SD=6.1, respectively) and academic achievement, however the neurocognitive profiles of the two groups differed significantly on multivariate analysis (F(24,31)=2.25, p =0.017). The group with schizophrenia performed significantly more poorly on tests of motor skills, verbal learning, and social cognition (effect sizes≥0.8) after correction for multiple comparisons. Other tests, but not the attentional measures used, showed nominally significant differences. Conclusions In adults with 22qDS, the pattern of neurocognitive differences between those with and without schizophrenia appears similar to that between patients with schizophrenia and controls. Attentional dysfunction may be a more general feature of 22qDS. The findings support 22qDS-schizophrenia as a genetic model for neurodevelopmental investigations of schizophrenia.