PURPOSE To quantitatively analyze and compare the novice vitreoretinal surgeons' performance after various types of external exposures. METHODS This prospective, self-controlled, cross-sectional study included 15 vitreoretinal fellows with less than 2 years of experience. Surgical performance was assessed using the Eyesi simulator after each exposure: Day 1, placebo, 2.5, and 5 mg/kg caffeine; Day 2, placebo, 0.2, and 0.6 mg/kg propranolol; Day 3, baseline simulation, breathalyzer reading of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentration; Day 4, baseline simulation, push-up sets with 50% and 85% repetition maximum; Day 5, 3-hour sleep deprivation. Eyesi-generated total scores were the main outcome measured (0-700, worst to best). RESULTS Performances worsened after increasing alcohol exposure based on the total score (χ2 = 7; degrees of freedom = 2; P = 0.03). Blood alcohol concentration 0.06% to 0.10% and 0.11% to 0.15% was associated with diminished performance compared with improvements after propranolol 0.6 and 0.2 mg/kg, respectively (∆1 = -22 vs. ∆2 = +13; P = 0.02; ∆1 = -43 vs. ∆2 = +23; P = 0.01). Propranolol 0.6 mg/kg was positively associated with the total score, compared with deterioration after 2.5 mg/kg caffeine (∆1 = +7 vs. ∆2 = -13; P = 0.03). CONCLUSION Surgical performance diminished dose dependently after alcohol. Caffeine 2.5 mg/kg was negatively associated with dexterity, and performance improved after 0.2 mg/kg propranolol. No changes occurred after short-term exercise or acute 3-hour sleep deprivation.