ObjectiveTo examine the feasibility and effects of a 12-week exercise intervention on physical performance, muscular strength, and circulating myokines in frail individuals living in nursing homes. DesignA cluster randomized, 2-period, 2-intervention crossover trial. Setting and ParticipantsFrail residents of 9 nursing homes were randomly assigned to either 12 weeks of concurrent exercise training (n = 5, 29 participants) or usual care (n = 4, 17 participants). The concurrent exercise training consisted of resistance and aerobic exercises (3 days/week). The usual care consisted of everyday routine and standard care. After a 4-week washout period, participants crossed to the other intervention. MethodsThe feasibility outcomes included recruitment rate, dropout rate and reasons, harms during the trial, adherence to exercise, and implementation cost. The primary endpoint was the change in physical performance measured by the Short Physical Performance Battery (SPPB). The secondary endpoints were changes in muscular strength (eg, handgrip strength, isokinetic knee extension, and flexion strength) and serum myokines concentration (myostatin and decorin). ResultsFrom the 46 participants enrolled (aged 70–99 years, 67.4% female), 34 completed the trial (26.1% dropout rate), the median adherence was 93.75%, and no adverse events occurred during the exercise sessions. The concurrent exercise training provided significant benefits over usual care on SPPB (B = 2.18; 95% CI, 1.35–3.00; P < .001), handgrip strength (B = 2.15; 95% CI, 1.00–3.30; P < .001), myostatin concentrations (B = −7.07; 95% CI, −13.48 to −0.66; P = .031) and myostatin-decorin ratio (B = −95.54; 95% CI, −158.30 to −32.78, P = .004). No significant between-group differences were found for the remaining secondary endpoints. Conclusions and ImplicationsThis concurrent exercise training is feasible, well-tolerated, and effective in improving physical performance, handgrip strength, myostatin, and myostatin-decorin ratio concentrations in frail older adults residing in nursing homes. These data reinforce the relevance of integrating exercise interventions in long-term care settings.