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Background: We have recently reported mutations in the cardiac sodium channel gene SCN5A in 5.9% of patients with atrial fibrillation (AF). In this study, we tested the hypothesis that mutations in sodium channel β subunit genes SCN1B-4B contribute to AF susceptibility. Methods and results: All 4 βsubunit genes were resequenced in 376 patients with AF (118 patients with lone AF and 258 patients with AF and cardiovascular disease) and 188 ethnically-defined controls. We identified 2 non-synonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF; these occur at residues highly conserved across mammals and were absent in controls. In 3 of 4 mutation carriers, there was saddle back type ST-segment elevation in the right precordial leads of electrocardiogram. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. To assess function in vitro , CHO cells were transfected with SCN5A without β subunit, SCN5A with wild-type (WT) β subunit, or SCN5A with mutant β subunit: all 4 mutants altered SCN5A current to a variable extent compared to WT β subunits. WT β1 increased SCN5A currents by 75%, and induced a negative shift in steady-state activation (−10.2 mV) and inactivation (−6.7 mV), compared to SCN5A alone. D153N β1 caused partial loss of function, with increased SCN5A current but to a smaller extent (24%) than WT β1, and a negative shift in steady-state activation (−12.1 mV) and inactivation (−8.1 mV) similar to WT. R85H β1 produced a pure loss of function, with currents no different from SCN5A alone. WT β2 did not change SCN5A current amplitude, while R28Q β2 and R28W β2 decreased current by 36% and 30%, respectively; and positively shifted steady-state activation by +7.4 mV and +5.1 mV, respectively, compared to WT. Conclusion: Loss of function mutations in sodium channel β subunits were identified in patients with AF, and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility.