Burkitt's lymphoma seems to be caused by Epstein-Barr virus (EBV). In Africa, more than 95% of patients harbor detectable EBV. In other parts of the world, the correlation is less clear; for example, about half of patients in South America seem to have an EBV infection and only about one third in North America.

There is considerable evidence that Burkitt's lymphoma is caused by EBV but while the virus is widespread, the lymphoma is restricted mostly to certain tropical regions in central Africa, South America and New Guinea. This lymphoma is a childhood disease with a peak at four to seven years and is rare over fifteen years or under a year. In some African countries, this is the most common childhood lymphoma and it appears to occur as outbreaks, again suggesting an infectious agent. This disease is also more common in poorer people.

Why is there this association with tropical areas? One idea is that malaria infection might be a co-factor. This is supported by the finding that the lymphoma was once common in areas with high rates of malarial infection (such as New Guinea) but has now greatly diminished. Other malaria-free areas have a lower incidence than nearby areas where malaria occurs. The tropical distribution of the tumor might also give a clue; incidence of Burkitt's lymphoma is lower in parts of the tropics where the temperature falls below 16 degrees. Thus, it is much less common in higher altitude regions of Africa. Also there is a higher incidence in wetter areas that might suggest a link to mosquito-borne malarial parasites and in some cases Burkitt's lymphoma is seasonal, coming in the rainy parts of the year.

There must be some other risk factors for getting the disease, however. It has been found that the incidence of Burkitt's lymphoma is much higher in areas of Africa where the milkbush  (Eurphorbia tirucalli) is found. Where this plant is rare, so is the disease. Milkbush, as its name implies, produces a white sticky sap and children often play with it. It is also used as a glue and to make medicines. Normally, EBV does not affect cells in culture but when even low concentrations of sap are added to the cells, the virus becomes activated and can then trigger neoplastic changes in the cells. It appears that something in the sap causes the transcription of three viral genes that allow the virus to replicate and infect more cells. Thus, a component of milkbush sap (and probably other Euphorbia species) may be a co-activator of EBV in causing the lymphoma.