Background: The 5-HT sub(1A) receptor subtype has been postulated to modulate aggressive behavior particularly when it is excessive. F15599 is a high affinity and selective 5-HT sub(1A) receptor agonist that exhibits biased agonism for postsynaptic receptors that are preferentially coupled to G alpha i3 protein subunits, with more potent action in the cortex, and with potential for selectively reducing aggression. Objectives and methods: The aims of the current study were to investigate the anti-aggressive effects of the novel 5-HT sub(1A) receptor agonist, F15599, microinjected into the ventral orbital prefrontal cortex (VO PFC) and into the infralimbic cortex (ILC) of CF-1 male mice that had been previously socially provoked and to confirm the specific action at this receptor by blocking its effects using the 5-HT sub(1A) receptor antagonist, WAY100,635. Results: Microinjection of the lower doses of F15599 (0.03 and 0.1 mu g) into the VO PFC, but not into the ILC, significantly reduced the frequency of attack bites and sideways threats, without affecting other elements of the behavioral repertoire related to aggression such as pursuing and sniffing the intruder and tail rattle. There were also no changes observed in the duration of walking and rearing. Pretreatment with WAY100,635 prevented the anti-aggressive effects of F15599 when microinjected into VO PFC. Conclusions: The present results demonstrated that F15599 is effective in reducing the most intense behavioral elements of aggressive behavior in male mice, when microinjected into the VO PFC, but not into the ILC, without affecting nonaggressive behavior, and confirmed the critical role of this cortical region and specifically the 5-HT sub(1A) heteroreceptors in the modulation of escalated aggressive behavior.