Catechol-O-methyltransferase is an important enzyme in the metabolism of dopamine and an important regulator of aspects of dopamine-dependent working memory in prefrontal cortex that are disturbed in schizophrenia. This study investigated the phenotype of mice with heterozygous deletion vs. homozygous knockout of the catechol-O-methyltransferase gene across paradigms that access processes relevant for psychotic illness. Homozygotes evidenced improved performance in spontaneous alternation, an index of immediate spatial working memory; this effect appeared more substantive in males and was reflected in performance in aspects of the Barnes maze, an index of spatial learning/memory. Heterozygotes evidenced impaired performance in object recognition, an index of recognition memory; this effect was evident for both sexes at a retention interval of 5 min but appeared more enduring in males. There were no material effects for either genotype in relation to sociability or social novelty preference. While homozygous catechol-O-methyltransferase deletion results in improvement in spatial learning/working memory with little effect on social behavior, heterozygous deletion results in impairment of recognition memory. We have reported recently, using similar methods, that mice with deletion of the schizophrenia risk gene neuregulin-1 evidence disruption to social behavior, with little effect on spatial learning/working memory. The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome.