Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been demonstrated to achieve the highest rates of arthrodesis in multilevel lumbar fusion but is also associated with possible perioperative morbidity. A novel allograft (OSTEOAMP) is a differentiated allograft that retains growth factors supporting bone healing. The authors sought to compare the clinical and radiographic outcomes of rhBMP-2 and the novel allograft in lumbar interbody arthrodesis to determine if the latter may be a safer and equally effective alternative to rhBMP-2 for single- and multilevel posterior or transforaminal lumbar interbody fusion (PLIF or TLIF). Patients who underwent single- or multilevel TLIF or PLIF using either OSTEOAMP or rhBMP-2 at the authors' institution over a 2-year period were prospectively followed for 12 months. Healthcare utilization, safety measures, patient satisfaction, physical disability (measured on the Oswestry Disability Index [ODI]), back and leg pain (on the numeric rating scale [NRS]), quality of life (on the EQ-5D scale), and return to work (RTW) were prospectively recorded. For purposes of this study, this consecutive series was retrospectively analyzed and pseudarthrosis rates were assessed at 2 years of follow-up. All patients (100%) had both 12-month patient-reported outcome follow-up and 24-month clinical and radiographic follow-up. One thousand one hundred fifty-four patients (654 treated with OSTEOAMP, 500 with rhBMP-2) were prospectively enrolled in the institutional registry. After propensity score matching, there were no significant baseline differences between 330 novel allograft and 330 rhBMP-2 cases. Perioperative morbidity and 90-day hospital readmission (3.3% vs 2.4%, p = 0.485) did not significantly differ between the novel allograft and the rhBMP-2 cases. At the 2-year follow-up, symptomatic pseudarthrosis requiring revision surgery occurred in 8 patients (2.4%) with OSTEOAMP and 6 patients (1.8%) with rhBMP-2 (p = 0.589). The overall fusion rate at 2 years was similar between groups (p = 0.213). Both groups showed significant and equivalent improvement in patient-reported outcome measures (PROMs) from baseline to 12-month follow-up, with no significant difference in 1-year mean NRS leg pain score (2.5 vs 2.7), ODI (25 vs 26), quality-adjusted life years (0.73 vs 0.73), satisfaction (83% vs 80%), or RTW (6.6 vs 7 weeks). In the authors' institutional experience, OSTEOAMP is a clinically viable substitute for rhBMP-2 for single- and multilevel lumbar fusion. This novel allograft provides clinically effective arthrodesis and improvements in PROMs comparable to rhBMP-2 with a similar safety profile. Additional indications and outcome assessment in longitudinal studies are needed to further characterize this allogeneic graft.