Hospitalization rates for respiratory syncytial virus (RSV) infection range from 1 to 20/1000 infants. To determine the rate and severity of RSV infections requiring hospitalization for infants in the Yukon-Kuskokwim (YK) Delta of Alaska, a 3-year prospective surveillance study was conducted. The annual rate of RSV hospitalization for YK Delta infants <1 year of age was 53-249/1000. RSV infection was the most frequent cause of infant hospitalization. RSV disease severity did not differ among non-high-risk infants in the YK Delta and at Johns Hopkins Hospital (JHH). On average, 1/125 infants born in the YK Delta required mechanical ventilation for RSV infection. During the peak season, approximately $1034/child <3 years of age was spent on RSV hospitalization in the YK Delta. In YK Delta infants </=6 months old, RSV microneutralizing antibody titers <1200 were associated with severe disease (odds ratio=6.2, P=.03). In the YK Delta and at JHH, newborns may be at greater risk for severe RSV illness than previously thought.