This study examined the relations of genetic variants in catechol-O-methyltransferase (COMT) gene, including rs737865 in intron 1, rs4680 in exon 4 (Val158Met) and downstream rs165599, to schizophrenia and its related neurocognitive functions in families of patients with schizophrenia. Totally, 680 individuals from 166 simplex (166 affected members and 354 nonpsychotic first-degree relatives) and 46 multiplex families (85 affected members and 75 nonpsychotic first-degree relatives) were interviewed using Diagnostic Interview for Genetic Studies, administered Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT), and drawn for venous blood. Both categorical (dichotomizing families on affected members' neurocognitive performance) and quantitative approaches toward the WCST and CPT performance scores were employed using the family-based association test and the variance components framework, respectively. Both false discovery rate and permutations were used to adjust for multiple testing. The genotypes of rs4680 were associated with both the WCST and CPT performance scores in these families, but not with schizophrenia per se in either whole sample or subgroup analyses. Meanwhile, the other two single nucleotide polymorphisms were differentially associated with the two tasks. For WCST indexes, regardless of subgroup analyses or quantitative approach, only rs737865 exhibited moderate associations. For CPT indexes, rs737865 exhibited association for the subgroup with deficit on CPT reaction time, whereas rs165599 exhibited association for the subgroup with deficit on CPT d' as well as quantitative undegraded d'. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions and hence conferring increased risk to schizophrenia.