Rifampin is a potent inducer of hepatic enzymes and is well documented to cause many clinically significant drug interactions. Studies in normal volunteers have shown its ability to decrease circulating levels of thyroid hormone, while having no effect on thyroid-stimulating hormone (TSH). Reports of rifampin's effects on patients on hormone replacement in the clinical setting are of interest since we believe only one such case has been described. We report the case of a man, stable on levothyroxine, who exhibited significantly elevated TSH levels during therapy with rifampin. Thyroid-stimulating hormone levels returned to baseline 9 days after discontinuance of rifampin.