Many human hereditary neurodegenerative diseases are caused by expanded CAG repeats, and anonymous CAG expansions have also been described in schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activated potassium channel (hSKCa3) that contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allele frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcoxon Rank Sum test, P=0.024), with CAG repeats longer than the modal value being over-represented in patients (Fisher Exact test, P=0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible association between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated K+ channels play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.