Purpose Autologous stem-cell transplantation (ASCT) has shown to provide curative benefit in patients with relapsed lymphoma and multiple myeloma (MM), often requiring hematopoietic support until marrow engraftment. Because of Jehovah's Witnesses' (JW) refusal of blood products, treatment challenges arise. This study represents 125 JWs with lymphoma (n = 55), MM (n = 68), or amyloidosis (n = 2), treated with high-dose chemotherapy (HDC) and ASCT without transfusions. Patients and Methods Priming with intravenous iron and erythropoietin occurred to increase hemoglobin (Hb) pretransplantation. Cytokine mobilization of stem-cells was used. Delay to HDC was done to allow Hb and platelets to approach 11 g/dL and 100 × 103/μL, respectively. Patients with MM received a standard dose of melphalan 200 mg/m2, with dose reduction for severe kidney dysfunction. Patients with lymphoma received carmustine 300 mg/m2, cyclophosphamide 1,500 mg/m2 on days 2 through 5 (total 6 g/m2), and etoposide 700 mg/m2 per day on days 2 through 4 (total 2,100 mg/m2). Post-transplantation, a combination of granulocyte colony-stimulating factor, erythropoietin, aminocaproic acid, and phytonadione was administered. Results There were two major and 15 minor bleeding complications, none occurring at platelets less than 5.0 × 103/μL, with six (4.8%) treatment-related mortalities. The median decrease in Hb was 5.0 g/dL, with median Hb nadir of 7.0 g/dL. The median number of days with platelet count less than 10 × 103/μL was 3, with median platelet nadir of 5.0 × 103/μL. Cardiac complications occurred in 40 patients (32%). Conclusion ASCT can safely be performed without transfusion support. A platelet transfusion trigger of ≤ 5 × 103/μL may be appropriate in select patients. Pharmacotherapy and cardiac monitoring are effective in the management of cardiac complications.