Detect and avoid (DAA) systems provide unmanned aircraft systems (UAS) with an alternative means of compliance with the see-and-avoid requirements associated with operations in the National Airspace System (NAS). Previous studies have examined the efficacy of different DAA alerting and guidance structures and formats. Prior research has also investigated the integration of DAA information with the alerting and guidance generated by the Traffic Alert and Collision Avoidance System (TCAS II). The next-generation replacement for TCAS II – the Airborne Collision Avoidance System X (ACAS X) – includes a variant to be used by UAS (ACAS Xu) that will provide both DAA and Collision Avoidance (CA) guidance. The alerting and guidance issued by ACAS Xu differs from previous DAA and CA systems, a result of new capabilities that were not available to earlier systems. Differences include the removal of warning-level DAA alerting and guidance, as well as the issuance of new types of CA guidance, referred to as Resolution Advisories (RAs). Whereas TCAS II only issues vertical RAs, ACAS Xu adds horizontal and blended (i.e., simultaneous vertical and horizontal) RAs. The current study assessed pilots' ability to respond to and comply with the DAA and RA alerting and guidance generated by ACAS Xu in a human-in-the-loop simulation. Sixteen active UAS pilots participated in the study and were tasked with responding to scripted DAA and RA traffic conflicts. Results showed that pilots were effective at making timely maneuvers against DAA threats. The proportion of losses of DAA well clear against noncooperative intruders was found to be significantly higher than the proportion of losses against cooperative intruders, a result of the limited declaration range of the simulated onboard RADAR. Results also demonstrated that pilots could consistently meet the five second response time requirement for initial RAs. Rapid responses to RAs had the corresponding effect of minimizing the severity of losses of DAA well clear. While pilots complied with initial RAs at a high rate, compliance dropped substantially when the target heading was updated during a horizontal RA. Pilot performance with ACAS Xu will be presented alongside results from prior DAA research.