The first two recognized cases of rapidly fatal hantavirus pulmonary syndrome in Pennsylvania occurred within an 8-month period in 1997. Illness in the two patients was confirmed by immunohistochemical techniques on autopsy material. Reverse transcription-polymerase chain reaction analysis of tissue from one patient and environmentally associated Peromyscus leucopus (white-footed mouse) identified the Monongahela virus variant. Physicians should be vigilant for such Monongahela virus-associated cases in the eastern United States and Canada, particularly in the Appalachian region.