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Efficient and safe mobilization of peripheral blood CD34⁺ stem cells is essential for successful autologous stem cell transplantation (ASCT) in patients with lymphoid malignancies. However, current mobilization strategies are often limited by suboptimal yield, significant toxicity, or high cost. We conducted a prospective observational study including 59 patients with lymphoma or multiple myeloma undergoing ASCT. Patients received fractionated intermediate-dose etoposide (175 mg/m² twice on days 1 and 2) followed by granulocyte colony-stimulating factor (G-CSF, 10 μg/kg daily). Mobilization efficacy, safety profile, and subsequent transplantation outcomes were evaluated. Successful mobilization (≥ 2 × 10⁶ CD34+ cells/kg) was achieved in 96.6% of patients within three days of apheresis. The median CD34⁺ cell yield was 5.35 × 10⁶ CD34+ cells/kg on the first day. Notably, 61.0% and 49.2% of patients collected ≥ 4 × 10⁶ and ≥ 6 × 10⁶ CD34⁺ cells/kg on the first day, respectively. Despite frequent grade 3-4 cytopenias, clinically significant complications were limited, with febrile neutropenia occurring in 16.9% of patients and no treatment-related mortality (TRM). All patients achieved neutrophil and platelet engraftment. Fractionated intermediate-dose etoposide combined with G-CSF achieved a high mobilization success rate, with most patients requiring a limited number of apheresis sessions and no TRM.