The chronic administration of guanethidine causes an immune-mediated destruction of sympathetic neurons in rats. Destruction can be prevented by various immunosuppressive agents, including gamma-irradiation and cyclophosphamide, as well as by administration with nerve growth factor (NGF). Experiments were conducted to determine whether: (1) NGF prevented accumulation of guanethidine within sympathetic neurons; and (2) NGF caused an inhibition of immune function by either blocking proliferation of immune-competent cells or by blocking effector function even in the presence of antigen and activated immune cells. NGF did not prevent accumulation of guanethidine within sympathetic ganglia in vivo, a necessary prerequisite for neuronal destruction, nor was it inhibitory on immune function using several assay systems. NGF, purified by either conventional methods or additionally by HPLC ("ultrapure'), did not inhibit either proliferation of cloned cytotoxic T lymphocytes (CTL) to antigen (class I major histocompatibility antigens) or lysis of target cells bearing the appropriate antigens. In addition, NGF did not exhibit growth stimulating effects in this assay system (i.e. it could not substitute for T cell growth factor). NGF also did not cause an inhibition of either murine or rat allogeneic mixed lymphocyte responses measured by lysis of appropriate target cells or proliferation, respectively. Finally, NGF did not inhibit, but rather appeared to stimulate the antibody response to sheep red blood cells generated in vivo in young rats. Thus NGF does not appear to prevent the immune-mediated neural destruction induced by guanethidine by acting as an immunosuppressive agent, but rather acts by some other mechanism such as preventing expression or recognition of antigen(s) on the sympathetic neuron.