Background:Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations.Methods:In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors.Results:Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis.Conclusions:Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant.Funding:Key Technological Projects of Guangdong Province grant 2018B030335001.Clinical trial number:NCT05265806