Lymphocytes infected with the intracellular parasite Theileria parva proliferate continuously as lymphoblastoid cell lines. We have previously shown that the continuous proliferation of the T. parva-infected (Tpi) cell line TpM(803) is mediated in part by an autocrine mechanism (Dobbelaere, D. A. E. et al., Proc. Natl. Acad. Sci. USA 1988. 85:4730). We now report that continuous proliferation also requires surface stimulation through cell-cell contact. Under standard culture conditions this surface stimulus is provided by the infected cells themselves, but it can also be provided by uninfected lymphocytes or macrophages. The ability to respond to surface stimulation is critically dependent on the presence of the parasite in the host cell and is lost within 48 h after the elimination of the parasite from the host cell cytoplasm by treatment with the theilericidal drug BW720c. Tpi cells also secrete a growth factor which is able to support the proliferation of diluted Tpi cells. Growth factor secretion is rapidly lost upon elimination of the parasite. Moreover, inhibition experiments using anti-interleukin 2 (IL 2) antibodies show that IL 2 is involved in the proliferation of the Tpi cell lines TpM(803) and IN10. T cell proliferation is dependent on a number of costimulatory signals which are normally provided by accessory cells. The finding that Tpi cells can mutually stimulate each other to grow in the absence of conventional accessory cells helps to explain how they can escape the normal constraints on T cell growth, allowing them to invade and multiply in non-lymphoid as well as lymphoid tissues.