On April 24, 2009, CDC reported eight confirmed cases of swine-origin influenza A (H1N1) virus (S-OIV) infection in Texas and California. The strain identified in U.S. patients was confirmed by CDC as genetically similar to viruses subsequently isolated from patients in Mexico. Since April 24, the number of cases in the United States and elsewhere has continued to rise. As of April 28, approximately half (45) of all U.S. cases of S-OIV infection had been confirmed among students and staff members at a New York City (NYC) high school. This report describes the initial outbreak investigation by the NYC Department of Health and Mental Hygiene (DOHMH) and provides preliminary details about 44 of the 45 patients (the remaining patient resides outside of NYC and was not included in the analysis). The preliminary findings from this investigation indicate that symptoms in these patients appear to be similar to those of seasonal influenza. DOHMH will continue monitoring for changes in the epidemiology and/or clinical severity of S-OIV infection.