Despite all scientific advances, infectious diseases are still the main cause of death in the world. Dengue is a Flavivirus serologically classified into four antigenically distinct types: DEN-1, 2, 3 and 4. These viruses are transmitted to humans by the mosquito Aedes aegypti infecting millions of people in tropical and sub-tropical regions of the world. Clinical manifestations can vary from asymptomatic to a severe infection leading to bleeding and shock (dengue hemorrhagic fever, DHF). Although DEN antigen and RNA have been detected in monocyte-macrophage, lung and liver of humans, infective viral particles could only be detected in the liver of people who presented DHF. Marked disturbance of liver functions indicating hepatocellular involvement were also observed. These findings sustain the hypothesis that liver is one of the most important sites for DEN replication. In order to get some insight about liver dysfunction following infection, we investigated some factors possibly involved in DEN induced cell death in a human hepatoma cell lineage model HepG2. Cells were grown on monolayers in an appropriated medium supplemented with 10% fetal bovine serum in a 5% CO₂ incubator. Sub-confluent cells were infected or mock infected and the assays were performed in different times. Our results showed that DEN promoted a significant reduction in cell viability after 12 hours of infection. After 24-48 hours, the percentage of viable cell had dropped to less than 30%, indicating a severe cellular dysfunction cause by infection. In agreement with this decrease in viability, DEN infection induced DNA fragmentation of HepG2 cells identified by TUNEL analysis. Additionally, infection promoted a significant decrease in mitochondria membrane potential, possibly indicating an altered function of this organelle. An interesting observation was that the decrease in cell viability was more pronounced following DEN-3 than after DEN-2 infection, since it required longer periods in order to DEN-2 to cause only a small decrease in this parameter. Taken together, our results indicate that both nuclear and mitochondria functions may be compromise in DEN infection and those events are indicative of the apoptotic process. Due to the differences observed following DEN-2 and DEN-3 infection, it seems that, at least in HepG2 cells, DEN induced cell dysfunction is serotype specific.