Oxytocin (OT) is a naturally occurring endogenous neuropeptide that is known to modulate social behavior across a wide range of animal species. We conducted a double-blind, placebo-controlled, pharmaco-functional magnetic resonance imaging (fMRI) study in which healthy normal subjects were randomized to treatment with either 24 IU intranasal OT (INOT; n=100) or placebo (PBO, n=104) and imaged with fMRI as they played an interactive social decision-making task known as the iterated Prisoner’s Dilemma (PD) game with same-sex partners. INOT altered the neural response to reciprocated cooperation (a positive social interaction) within areas involved in reward and salience such as the nucleus accumbens and dorsal ACC, and also altered the response to unreciprocated cooperation (a negative social interaction) within areas involved in salience and threat detection, like the anterior insula and the amygdala. Furthermore, INOT altered functional connectivity within a social behavioral neural network in response to both reciprocated and unreciprocated cooperation. These findings support the potential utility of OT to treat stress and anxiety disorders as well as disorders involving deficits in social motivation. However, INOT effects were highly heterogeneous, depending on sex, OXTR genotype, and stimulus novelty vs. familiarity. Furthermore, effects may also differ by dose, patient status (healthy subjects vs. patients) and between endogenous and exogenously administered OT.