Deficiency in factors IX and X may be an under recognized, yet serious complication of amyloid light-chain (AL) amyloidosis. Herein, we report the first case with a combined acquired severe deficiency in FX and mild deficiency in FIX due to AL amyloidosis managed using prophylactic FIX and FX therapy plus chemoimmunotherapy. While in vivo recovery results after FIX administration were in accordance with drug label data, doses required to attain activity concentrations of FX necessary to achieve clinical hemostasis exceeded current drug label recommendations by 2-fold, and as such, are the highest ever reported. Our pharmacokinetically-directed high-dose factor X replacement therapy was safe and effective in preventing and treating bleeding associated with the acquired deficiency. Combined chemoimmunotherapy using daratumumab + CyBorD was able to restore hemostasis allowing for cessation of prophylactic factor therapy. Moreover, the patient’s original prognosis of roughly 9 months markedly improved, and to date, he is now 48 months out from the original diagnosis. Further study is needed to characterize the incidence of acquired factor deficiencies in patients with AL amyloidosis and the optimal clotting factor replacement strategy to prevent and treat bleeding during procedures and cancer-directed chemoimmunotherapy.