The etiology of mood disorders remains elusive, despite our increasing understanding of the neurotransmitter systems and brain regions that are involved. We performed a large family-based association study to test if the human kainate receptor GluR7 gene (GRIK3) is associated with bipolar disorder (BP) or recurrent major depressive disorder (R-MDD). One hundred fifty-three multiplex BP families from the National Institute of Mental Health (NIMH) Genetics Initiative on Bipolar Disorder were analyzed with the transmission disequilibrium test (TDT). We detected a significant linkage disequilibrium (LD) indicated by preferential maternal transmission of the GluR7 S310 allele to R-MDD patients (P = 0.012), but not to bipolar I disorder (BPI) patients (P = 1.00). We performed a second independent study by applying the TDT in 81 parent-offspring triads from families that inherit recurrent early-onset major depressive disorder (RE-MDD). The results from this second study showed only a suggestive maternal association (P = 0.068). Our findings imply that the GluR7 gene is a susceptibility factor in R-MDD and that the glutamatergic receptor system plays a critical role in the disease etiology.