To investigate the levels of the capsaicin or vanilloid receptor-1 (VR1) and the ATP-gated purinoceptor P2X3 in painful and nonpainful human tooth pulps. Immunohistochemistry with specific antibodies and image analysis was used to quantify VR1- and P2X3-positive nerve fibers in painful (n = 13) and nonpainful (n = 33) human tooth pulps, and VR1 immunoreactivity was compared with immunoreactivity for the structural neuronal marker peripherin. Strong VR1-like immunoreactivity was documented for the first time in dental pulp neurons. Weaker P2X3-like immunoreactivity was also detected in fewer nerve fibers. The ratio of VR1 to peripherin immunoreactivity was not significantly different between nonpainful and painful tissues (mean +/- SE% area of VR1 to peripherin; nonpainful 53.4 +/- 4.7%, n = 33; pulpitis 35.1 +/- 7.1%, n = 13; P = .07). The presence of VR1 and P2X3 in fibers of human tooth pulp suggest that they may play a role in perception of dental pain, but further studies, including quantitation of their ligands, are necessary to elucidate any role they may play in pathophysiologic states.