BACKGROUND In April 2009, an outbreak of novel swine-origin influenza A (2009 H1N1 influenza) occurred at a high school in Queens, New York. We describe the outbreak and characterize the clinical and epidemiologic aspects of this novel virus. METHODS The New York City Department of Health and Mental Hygiene characterized the outbreak through laboratory confirmation of the presence of the 2009 H1N1 virus in nasopharyngeal and oropharyngeal specimens and through information obtained from an online survey. Detailed information on exposure and the onset of symptoms was used to estimate the incubation period, generation time, and within-school reproductive number associated with 2009 H1N1 influenza, with the use of established techniques. RESULTS From April 24 through May 8, infection with the 2009 H1N1 virus was confirmed in 124 high-school students and employees. In responses to the online questionnaire, more than 800 students and employees (35% of student respondents and 10% of employee respondents) reported having an influenza-like illness during this period. No persons with confirmed 2009 H1N1 influenza or with influenza-like illness had severe symptoms. A linkage with travel to Mexico was identified. The estimated median incubation period for confirmed 2009 H1N1 influenza was 1.4 days (95% confidence interval [CI], 1.0 to 1.8), with symptoms developing in 95% of cases by 2.2 days (95% CI, 1.7 to 2.6). The estimated median generation time was 2.7 days (95% CI, 2.0 to 3.5). We estimate that the within-school reproductive number was 3.3. CONCLUSIONS The findings from this investigation suggest that 2009 H1N1 influenza in the high school was widespread but did not cause severe illness. The reasons for the rapid and extensive spread of influenza-like illnesses are unknown. The natural history and transmission of the 2009 H1N1 influenza virus appear to be similar to those of previously observed circulating pandemic and interpandemic influenza viruses.