OBJECTIVES:  Pertussis incidence has resurged in the US after a nadir in the 1970s and is now one of the most prevalent vaccine-preventable infections. Infants are at greatest risk for severe pertussis-related morbidity and mortality (~50% of infant cases require hospitalization) and account for the majority of cases. We sought to quantify the cost and mortality burden of infant pertussis cases severe enough to prompt hospitalization. METHODS: Data on pertussis-related hospitalizations (ICD-9-CM discharge codes 033.0, 033.8, 033.9, 484.3) from the 2000-2010 Nationwide Inpatient Sample (NIS) were retrospectively analyzed. Charges were converted to costs using a 0.5 cost-to-charge ratio. Weighted, nationally representative estimates of costs per admission (in 2013 US dollars), length of stay (LOS), and case fatality rates (CFRs) were descriptively assessed for each year. RESULTS: Total numbers of infant pertussis hospitalizations in the US followed a cyclic pattern, starting at 2,282 in 2000 and peaking at 5,343 in 2005, then declining to 1,614 in 2007 before another peak of 3,220 in 2010. Mean [SD] LOS for these hospitalizations fluctuated minimally year-to-year, but an overall (albeit modest) increase was observed: from 3.3 [7.3] days in 2000 to 3.9 [9.5] days in 2010. Mean [SD] cost per admission increased at a greater rate than LOS, from $12,377 [$23,985] in 2000 to $16,339 [$37,224] in 2010. Both LOS and costs were more than double those observed for non-pertussis hospitalizations. CFRs were relatively stable during the period, fluctuating between ~1.5% and 3%, although a peak of 4.4% occurred in 2005 coinciding with the incidence peak. CONCLUSIONS: Infant pertussis hospitalizations typically exceed 3 days and are associated with high costs compared with hospitalizations for other causes. Observed CFRs were consistent with the ~2% fatality rate previously derived from CDC surveillance. These data may help inform economic and cost-effectiveness evaluations of future pertussis vaccination programs.