Background: Oxytocin is a neuropeptide known for its prosocial properties and role in social bonding, and intervention with intranasal oxytocin is posited to modulate affective and social cognition (i.e., hot cognition). Serotonin (5-HT) neurotransmission is also involved in emotional and social behaviors and appear to work in concert with oxytocin. However, this interaction so far remains elusive in humans. Therefore, we here investigate the relation between brain 5-HT 4 receptor (5-HT₄R) levels and oxytocin-modulated hot cognition. Methods: Using a double blind, placebo-controlled, randomized crossover design, 35 healthy women received a dose of 24 IU intranasal oxytocin or placebo one month apart. The women were naturally cycling and to control for hormonal fluctuations across the menstrual cycle, intervention days were placed during the early follicular phase. Following intervention cognitive domains including affective memory, affective bias in emotion processing, moral emotions and social information preference were assessed. In a subgroup (n = 25), Positron Emission Tomography (PET) was used to image 5-HT₄R brain binding at baseline with the [¹¹C]SB207145 radiotracer. Results: No effect of oxytocin intervention relative to placebo was observed for any of the cognitive outcomes. Likewise, regional brain 5-HT₄R binding at baseline was not associated with cognitive responses to oxytocin intervention. Conclusion: Our data suggest that intervention with intranasal oxytocin does not have an overall effect on hot cognition in healthy women and further that 5-HT₄R brain architecture does not mediate cognitive effects of oxytocin in the healthy state.