Background Monoresistance to rifamycins necessitates longer and more toxic regimens for tuberculosis (TB). We examined characteristics and mortality associated with rifampin-monoresistant (RMR) TB in the United States. Methods We analyzed Mycobacterium tuberculosis culture-positive cases reported to the National TB Surveillance System (excluding California because HIV infection was not reported to CDC during 2005-2010) between 1998 and 2014. We defined: (1) RMR TB found on initial drug susceptibility testing (DST), and (2) possible acquired rifampin-resistant (ARR) TB. We assessed temporal trends in RMR TB. For both classifications of rifampin resistance, we calculated adjusted risk ratios (adjRR) and 95% confidence intervals (CI) for social and clinical characteristics associated with mortality when compared to drug-susceptible TB in multivariable models using backwards selection. Results Of 180,329 TB cases, 126,431 (70%) cases were eligible for analysis, with 359 (0.28%) of eligible cases reported as RMR. The percentage of RMR TB cases with HIV declined 4% annually during 1998–2014. Persons with HIV and prior TB were more likely to have RMR TB (adjRR=25.9, CI=17.6–38.1), as were persons with HIV and no prior TB (adjRR=3.1, CI=2.4–4.1), versus those without either characteristic, controlling for other statistically significant variables. RMR cases had greater mortality (adjRR=1.4, CI=1.04–1.8), controlling for HIV and other variables. Persons with HIV had greater risk of ARR than persons without HIV (adjRR=9.6, CI=6.9–13.3) and ARR was also associated with increased mortality, controlling for HIV and other variables. Conclusions All forms of rifampin resistance were positively associated with HIV infection and increased mortality.