Background Critical illness may weaken muscles, with long-term consequences. Objective To assess physiological responses to an early standardized passive exercise protocol to prevent muscle weakness in adults receiving mechanical ventilation. Methods A quasi-experimental within-subjects repeated- measures design was used. Within 72 hours of intubation, 30 patients had 20 minutes of bilateral passive leg movement delivered by continuous-passive-motion machines at a standardized rate and flexion-extension. Heart rate, mean blood pressure, oxygen saturation, and cytokine levels were measured before, during, and after the intervention. The Behavioral Pain Scale was used to measure patients' comfort. Repeated- measures analysis of variance was used to analyze the effect of the exercise on independent variables. Results Patients were mostly white men with a mean age of 56.5 years (SD, 16.9) with moderate mortality risk and illness severity. Heart rate, mean blood pressure, and oxygen saturation did not differ from baseline at any time measured. Pain scores were significantly reduced (/r243 70 42 = 4-08; p=-°2) 5 and 10 minutes after exercise started and remained reduced at the end of exercise and 1 hour later. Interleukin 6 levels were significantly reduced (F., 60431 =4.35; P=.O3) at the end of exercise but not after the final rest period. Interleukin 10 levels did not differ significantly. Ratios of interleukin 6 to interleukin 10 decreased significantly (F, 61 4338 = 3.42; P=.O5) at the end of exercise and again after 60 minutes' rest. Conclusion The exercise was well tolerated, and comfort improved during and after the intervention. Cytokine levels provided physiological rationale for benefits of early exercise. {American Journal of Critical Care. 2013;22:337-349)