Two major subtypes of respiratory syncytial virus have been identified. This study assessed the hypothesis that A-subtype infections were more severe than B-subtype infections among the 157 infants hospitalized in two hospitals in Rochester, N.Y., during two winters. Severity was measured both by specific clinical observations and by a severity index that was derived empirically. Among all subjects, several clinical observations suggested that A-subtype infections were more severe. For example, mechanical ventilation was required in 12.6% of those with A-subtype compared with 1.6% of those with B-subtype infection (relative risk = 7.88; p = 0.01). Among high-risk infants (infants with underlying conditions or age 3 months or less at admission), carbon dioxide tension greater than 45 mm Hg was found in 37.0% of those with A-subtype compared with 12.0% of those with B-subtype infection (relative risk = 3.08; p = 0.04). In discrete multivariate (logit) analysis, effects of subtype (odds ratio = 6.59; p less than 0.01) on severity remained after adjustment for other statistically significant effects of age less than 3 months, underlying condition, and premature birth. The finding that A-subtype infections were more severe might have important implications for vaccine development, studies of the virulence of respiratory syncytial virus, clinical management (e.g., selection for antiviral therapy), and long-term prognosis.