The evolution of dengue virus (DENV) is characterized by phylogenetic trees that have a strong temporal structure punctuated by dramatic changes in clade frequency. To determine the cause of these large-scale phylogenetic patterns, we examined the evolutionary history of DENV serotype 1 (DENV-1) and DENV-3 in Thailand, where gene sequence and epidemiological data are relatively abundant over a 30-year period. We found evidence for the turnover of viral clades in both serotypes, most notably in DENV-1, where a major clade replacement event took place in genotype I during the mid-1990s. Further, when this clade replacement event was placed in the context of changes in serotype prevalence in Thailand, a striking pattern emerged; an increase in DENV-1 clade diversity was associated with an increase in the abundance of this serotype and a concomitant decrease in DENV-4 prevalence, while clade replacement was associated with a decline in DENV-1 prevalence and a rise of DENV-4. We postulate that intraserotypic genetic diversification proceeds at times of relative serotype abundance and that replacement events can result from differential susceptibility to crossreactive immune responses.Dengue is one of the most important reemerging viral diseases, promulgated by increases in human population size and the expansion of global travel networks (10), coupled with the possibility that global climatic changes alter the distribution of the mosquito vector (11,14). Although most cases of dengue virus (DENV) infection are subclinical or cause a febrile illness that is rarely fatal (dengue fever [DF]), increasingly large numbers of patients experience the more severe form of the illness, dengue hemorrhagic fever (DHF), associated with plasma leakage and hemorrhage. With a tendency to progress into fatal shock (dengue shock syndrome), case fatality rates of DHF/dengue shock syndrome vary from 1 to 5% (42). DENV is transmitted among humans primarily by the peridomestic mosquito species Aedes aegypti, although a transmission cycle involving sylvatic Aedes species and nonhuman primates has been described in parts of Africa and Asia (8,21,29). Genetically, DENV is a single-stranded, positive-sense RNA virus with a genome of approximately 11 kb that encodes 10 proteins translated as a single open reading frame and classified within the Flaviviridae. It is subdivided into four serotypes, denoted DENV-1 to DENV-4, that now cocirculate in many parts of the tropical and subtropical world. Importantly, there is growing epidemiological evidence that synergistic host interactions in response to these serotypes following sequential infection, vis-à-vis "antibody-dependent enhancement," are instrumental in the pathophysiology of DHF (16, 34). As such, the study of epidemiological dynamics in populations in which DENV serotypes cocirculate is of special significance.In recent years, there has been considerable interest in describing the genetic structures of DENV populations and determining their underlying evolutionary processes (13,27). These ...