In 2001, increased activity of the rarely detected enterovirus echovirus type 13 (E13) was observed in the United States. This article describes the epidemiologic, clinical, and genetic characteristics of E13 activity in the United States in 2001, compared with E13 activity abroad in 2000-2002. In the United States, E13 accounted for 376 (24%) of the 1584 enterovirus isolates reported in 2001 (29% of the reported isolates had a known serotype), compared with 74 isolates reported during 1970-2000. Five states reported aseptic meningitis outbreaks associated with E13, for a total of 521 cases. All characterized E13 isolates from the United States, Europe, Asia, and Oceania recovered in 2000-2002 were at least 95% identical to each other in VP1 capsid gene sequence, but they were genetically distinct from E13 isolates recovered before 2000. Continued surveillance of enteroviruses is important to alert physicians and public health officials to changes in disease trends and to improve efficiencies of clinical intervention.