Abstract: Objective To investigate the effect and safety of frailty treatment with BupiYishen prescription in older frail patients aged over 65 years. Methods One hundred and twenty older frail patients (65-91 years old) were randomly divided into therapy group and control group with 60 of each. The control group was received only western medicine treatment. In addition to western medicine treatment, therapy group was received BupiYishen prescription, one agent per day. The agent was decocted with water for oral intake, and twice a day, 150 mL each time. Before and 12 weeks after treatment, scores of Fried frailty criteria, serum levels of nutrition-related proteins and clinical adverse reactions were observed. Results After treatment for 12 weeks,compared with control group (3.0±1.4), frailty scores of therapy group (2.6±1.2) decreased more significantly (P<0.05). In the therapy group, compared with levels of serum prealbumin [PA, (213.49±46.29) mg/L], albumin [ALB, (37.47±3.28) g/L] and retinol binding protein [RBP, (39.30±10.38) mg/L] before the treatment, 12 weeks after the treatment, levels of PA [(231.98±52.75) mg/L], ALB [(40.06 ±3.44) g/L], RBP [(44.39±15.56) mg/L] increased more significantly (P<0.05). No severe adverse reactions were found in both groups. Conclusion BupiYishen prescription can safely enhance clinical efficacy for the treatment of frailty. Results of the investigation may provide some reference to the prevention and treatment of frailty.