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With high mutation rates, large population sizes, and rapid turnover, RNA viruses can evolve over the course of individual infections. While the dynamics of viral evolution under selective pressures from host immunity has been described for chronic infections, such as those from HIV and HCV, the extent and nature of viral diversification in acute viral infections remains uncharacterized. Here, we investigate the within-host diversification of human respiratory syncytial virus (RSV), a highly prevalent cause of respiratory infections, in healthy adults who were experimentally infected with identical virus and in infants hospitalized with severe manifestations of naturally acquired infections. In aggregate, viral diversification in the adults peaked at day 3, with statistically significant overrepresentation of diversity in the matrix protein 2 (M2) and non-structural protein 2 (NS2) genes. A later peak in diversity at day 10 was attributable to a single study subject, with diversity predominantly in known and predicted B and T cell epitopes. In the infant infections, much less diversity was observed, possibly related to sampling starting at the time of diagnosis and hospitalization, and trended towards overrepresentation in the G surface protein. Our findings raise the possibility of multiple mechanisms for control of RSV infection that vary over the course of an infection and by host, and establish a framework for further investigation into the basis of heterogeneous host response to infection. Moreover, the results have broad implications for investigations into immune response and the use of deep sequencing in viral pathogenicity and the molecular epidemiology of pathogen spread.