In this paper, the compatible solute betaine is investigated for its antagonistic effects toward sodium toxicity in anaerobic methanogenic systems. Concentrations of betaine as low as 1 mM are shown to be effective at reducing the toxicity symptoms of high concentrations of sodium in the following anaerobic reactor systems: batch reactors seeded with a Methanosarcina enriched culture and batch reactors seeded with a Methanothrix culture, where the acclimation time or lag time before methane production begins is reduced significantly; CSTRs, where the acetic acid uptake rate increases dramatically; fluidized bed reactors, where gas production and pH increase and effluent COD and volatile acid concentration decrease; and UASB reactors, where gas production increases markedly. Because the phenomenon of sodium toxicity antagonism by betaine was demonstrated in anaerobic batch reactors, CSTRs, fluidized bed reactors, and UASB reactors, the usefulness of betaine in an industrial application may be feasible.