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This cross-sectional study was conducted at the Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia, with the purpose of comparing the differences between male and female medical students regarding detecting the level of perceived stress and assessing the factors associated with the perceived stress.Students were selected through a stratified random sample with proportional allocation for different academic years (all years), with a final total sample size of 173 males and 173 females. Sociodemographic data of the students were recorded. Perceived stress was measured by using the Perceived Stress Scale. Social support was assessed among medical students by using the Multidimensional Scale of Perceived Social Support.The severity of perceived stress was significantly higher among female medical students compared with male medical students (P=0.005). Female medical students showed a significantly poor friend support (with their female friends) compared with male medical students (P=0.001). Poor friend support was the only significant predictor for increased perceived stress among female medical students (B=−0.24, P=0.002).The current study demonstrated that stress was significantly higher among female medical students compared with male medical students. Poor friend support was the only significant predictor for increased perceived stress among female medical students. Parental restrictions, represented specifically as parents’ attitude toward their daughters against having direct and easy social communication with their female friends, may be considered as a factor that could explain poor friend support among female medical students in Saudi Arabia.