High-dose niacin has versatile and substantial efficacy for the treatment of hyperlipidemias, but its utility is compromised by various side effects, the most serious of which is liver damage. It is proposed that this hepatotoxicity reflects the high demand for methyl groups imposed by niacin catabolism, leading to a reduction in hepatic levels of S-adenosylmethionine (SAM). Depletion of the hepatic SAM pool has likewise been shown to mediate, at least in part, the hepatotoxic effects of ethanol, methotrexate, and niacinamide. If niacin does indeed decrease SAM, a likely consequence would be a counterproductive elevation of plasma homocysteine. Conceivably, methyl group deficiency, by altering membrane properties of skeletal muscle, also contributes to niacin-induced insulin resistance. Concurrent betaine supplementation - preferably administered as a complex with equimolar amounts of niacin - may represent the most cost-effective way to prevent niacin-mediated depletion of SAM and thus avoid hepatotoxicity (and possibly other adverse effects) while controlling homocysteine. Betaine also merits evaluation as an adjuvant to methotrexate and niacinamide therapies.