Objective: Investigate the feasibility of a nurse-led mobility protocol and compare the effects of once- versus twice-daily episodes of early therapeutic mobility (ETM) and low- versus moderate-intensity ETM on serum biomarkers of inflammation and selected outcomes in critically ill adults. Design: Randomized interventional study with repeated measures and blinded assessment of outcomes. Setting: Four adult intensive care units (ICUs) in two academic medical centers. Subjects: Fifty-four patients with > 48 hr of mechanical ventilation (MV). Intervention: Patients were assigned to once- or twice-daily ETM via sealed envelope randomization at enrollment. Intensity of (in-bed vs. out-of-bed) ETM was administered according to protocolized patient assessment. Measurements: Interleukins 6, 10, 8, 15, and tumor necrosis factor-α were collected from serum before and after ETM; change scores were used in the analyses. Manual muscle and handgrip strength, delirium onset, duration of MV, and ICU length of stay (LOS) were evaluated as patient outcomes. Main Results: Hypotheses regarding the inflammatory biomarkers were not supported based on confidence intervals. Twice-daily intervention was associated with reduced ICU LOS. Moderate-intensity (out-of-bed) ETM was associated with greater manual muscle test scores and handgrip strength and reduced occurrence of delirium. Conclusion: Findings from this study suggest that nurses can provide twice-daily mobility interventions that include sitting on the edge of the bed once patients have a stable status without altering a pro-inflammatory serum biomarker profile.