Substance P (SP) and SP(4-11) stimulated significantly the proliferation of human T lymphocytes in vitro at respective concentrations of 10(-11) M to 10(-7) M and 10(-9) M to 10(-7) M, as assessed by the uptake of [3H]thymidine and [3H]leucine. The proliferative response of human T lymphocytes to PHA was augmented by 10(-9) M to 10(-8) M SP and 10(-10) M to 10(-7) M SP(4-11). The inactive analogue [D-Pro2, D-Phe7, D-Trp9]-SP inhibited the effects of SP on T lymphocytes. The specific stimulation of T lymphocytes by SP suggests a unique mechanism for the regulation of immunologic responses by peripheral nerve-derived factors.