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A recent epidemic of malaria in the highlands of Bolivia and establishment of multiple Anopheles species mosquitoes in the highlands of Ecuador highlights the reemergence of malaria in the Andes Mountains in South America. Because malaria was endemic to many highland valleys at the beginning of the 20th century, this review outlines the 20th century history of malaria in the highlands of Ecuador, and focuses on its incidence (e.g., geographic distribution) and elimination from the northern highland valleys of Pichincha and Imbabura and the role of the Guayaquil to Quito railway in creating highland larval habitat and inadvertently promoting transportation of the vector and parasite. Involvement of control organizations in combating malaria in Ecuador is also outlined in a historical context. Some authors have speculated that Anopheles mosquitoes may begin transmitting malaria parasites (Plasmodium spp.) at higher altitudes in the South American Andes because of climate change (1,2). In contrast, highland malaria in Africa has more often been attributed to land use alterations, malaria treatment resistance, changes in vector control measures, and human migration into foothill and mountainous regions (3). Before 2004, a short-lived epidemic of P. vivax malaria was recorded in a village in Bolivia at an altitude of 2,300 m that was transmitted by Anopheles pseudopunctipennis Theobald mosquitoes (4). Multiple anopheline malaria vectors have also become established in the highlands of Ecuador (5). In this review, we summarize documented cases of highland malaria that occurred in Ecuador during the early 20th century. We defi ne the term highland malaria to mean all malaria that occurs in regions with steep topography. Using geographic information systems (ArcGIS versio