The demand for United States Air Force (USAF) remotely piloted aircraft (RPA) intelligence, surveillance, reconnaissance (ISR) and weapons-strike operations has led to the necessity of sustaining around-the-clock operations across the globe. Because of the unique nature of RPA operations, there is a wide range of opinions among military and medical leadership as to the sources, levels, and impact of stress affecting performance capabilities among RPA operators (pilots, sensor operators, and mission intelligence coordinators). The purpose of this study is to (a) identify main sources of self-reported occupational stress, (b) use standardized selfreport questionnaires to identify rates of clinical distress and post-traumatic stress disorder (PTSD), (c) compare findings with local non-RPA operator airmen (logistics and support units from the same geographic locations), and (d) identify demographic and occupational stressors that correlate with (or are predictive of) clinical distress and PTSD among Predator/Reaper operators. Participants included 670 USAF RPA Predator/Reaper operators and 751 noncombatant airmen. Each participant completed a demographics questionnaire, items assessing their top sources of occupational stress, and standardized instruments assessing emotional distress and PTSD. Participation was encouraged by line leadership, and responses to the survey were anonymous to maximize self-disclosure. The most commonly cited stressors among RPA operators included long hours, shift work, deployed ingarrison status, ergonomic design of the ground control station, and sustaining vigilance to large amounts of real-time visual and auditory data. Combat-related stressors were not rated as top sources of stress. Rates of clinical distress and PTSD were higher among RPA operators (20% and 5%, respectively) in comparison to non-RPA airmen (11% and 2%, respectively). Given the challenging nature of sustaining around-the-clock missions, the results of this study suggest RPA operators should have regular access to mental health care. Military leadership recommendations were developed from study results to optimize performance and occupational climate for USAF ISR weapons-deploying RPA platforms.