BACKGROUND: This study examined whether intranasal oxytocin enhances the stress-buffering effects of social support during experimentally induced pain, taking into account the role of individual differences in attachment security. METHODS: Female participants (N = 193) were randomly assigned to oxytocin (24 IU intranasal) or placebo and to receive support or no support from a friend (2 x 2 factorial design with repeated measures)). Participants underwent the Cold Pressor Task (CPT) and were monitored for heart rate variability (HRV: RMSSD) and heart rate and reported pain levels. The Experiences in Close Relationships Questionnaire was used to measure attachment. RESULTS: Oxytocin reduced RMSSD (p = 0.003, partial n(2) = 0.03) and increased heart rate (p = 0.039, partial n(2) = 0.03) in individuals who received support, possibly reflecting an enhanced attentional state. Oxytocin did not enhance beneficial effects of social support on perceived pain, but increased pain intensity in avoidantly attached individuals who were supported by a friend (p = 0.009, partial n(2) = 0.06). LIMITATIONS: Only female participants were examined. Future studies are needed to determine sex differences in how oxytocin shapes stress-buffering effects of support. CONCLUSIONS: Oxytocin may enhance the salience of social proximity and may be a mechanism underlying previously reported social influences on cardiovascular and mental health. However, oxytocin effects depend on interpersonal insecurities and may trigger discomfort in avoidantly attached individuals. Caution about oxytocin\'s therapeutic promise is warranted.