Burkitt lymphoma (BL) cells are highly sensitive to suboptimal growth conditions and undergo apoptosis when seeded at reduced serum concentration or low cell density. Irradiated fibroblasts can protect BL cells from apoptosis induced by lowering the serum concentration or cell density through secretion of a survival- and proliferation-promoting activity which is soluble and labile. Murine B cells have a restricted uptake capacity for cystine and require cysteine for proliferation, which can be supplied efficiently by feeder cells. Therefore, we have studied the role of cysteine and other compounds with free thiol groups for survival and proliferation of BL cells. Cysteine, when added alone, exerted strong toxicity on BL cells. This toxicity could be counteracted by the addition of catalase, pyruvate or bathocuproine disulfonate (BCS), all of which interfere with the production of hydrogen peroxide. Inhibition of the toxicity of cysteine was necessary to unravel the survival- and growth-promoting activity of cysteine at low cell density. Alpha-thioglycerol, beta-mercaptoethanol and dithiothreitol had similar toxic activity in the absence of catalase, pyruvate and BCS and, through stimulation of cysteine uptake and glutathione synthesis, displayed a similar survival- and growth-promoting activity in the presence of the protective agents. The survival- and proliferation-inducing activity of thiol compounds in the presence of catalase, pyruvate and BCS was not associated with induction of BCL-2 or BAX. Cysteine/cystine uptake and the intra/cellular glutathione level are thus important parameters, determining the susceptibility vs. resistance of BL cells to apoptosis.