Resident physicians are the first-line health service providers, subjected to prolonged working hours, sleep deprivation and high job demands. Work stress causes reduction in productivity, suboptimal patient care and medical errors. To determine the level of stress among residents and associated factors and stressors. A cross-sectional study at Tanta University Hospitals recruited residents (n = 278), between December 2016 and February 2017. Job stress was assessed using a predesigned questionnaire. The mean age was 26.53 ± 1.35, and 46.4% were males. The majority reported they work more than 48 h/week, do not get a break during work and have a night shift periodically (87%, 83.1% and 94.2%, respectively). Only 4 (1.4%) had low stress while 169 (60.8%) had moderate and 105 (37.8%) had high stress. The study revealed a statistically significant association between high level of stress and being a single resident (p = 0.017), belonging to surgical departments (p = 0.001) and an absence of break during working hours (p = 0.001). The prime sources of stress were underpayment for the job (87.4%), serving to large number of patients (85.2%), disruption of home life due to long hours at work (83.9%), conflict of responsibilities (81.3) and complying with increasing bureaucratic procedures (78.8%) besides no available fund for research (74.8%). Medical residents experienced moderate to high level of job stress. Thus, there is a need for stress management programs during residency training period taking in consideration main sources of stress.