This randomized trial assessed the effect of recombinant human erythropoietin (EPO) vs preoperative autologous donation (PAD) on postoperative vigor and handgrip strength in patients undergoing primary total joint arthroplasty. Adults with baseline hemoglobin level of 11 to 14 g/dL received EPO (600 IU/kg once weekly for 4 doses, n = 130) or PAD (n = 121) before primary, unilateral hip or knee arthroplasty. Mean changes in vigor score and handgrip strength from baseline were not significantly different between treatment groups. Multivariate analyses found a significant treatment effect favoring EPO over PAD for vigor, but not for handgrip strength. Patients in the EPO group had higher hemoglobin levels and required fewer transfusions. Both treatments were well tolerated. Additional study is needed to elucidate the influence of blood management strategies on postoperative vigor.