BACKGROUND: The effect of a peritransplant multidirectional walking intervention to target losses in physical function and quality of life (QOL) has not been investigated. PURPOSE: This study examined the effects of a novel multidirectional walking program on physical function and QOL in adults receiving a hematopoietic stem cell transplant (HSCT). METHODS: Thirty-five adults receiving an autologous or allogeneic HSCT were randomized to a multidirectional walking (WALK) or usual care (CONT) group. The WALK group received supervised training during hospitalization; the CONT group received usual care. Patients were assessed at admission (t0), 3 to 5 d post-HSCT (t1), and 30 d post-HSCT (t2). Physical function measures included the 6-min walk test (6MWT), the Physical Performance Test, and the Timed Up and Go test. Health-related QOL was collected using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire. RESULTS: There were no significant between-group changes for physical function or QOL. However, after the intervention (t1 to t2), the WALK group showed significant improvement in aerobic capacity (6MWT, P = 0.01), physical (P < 0.01) and functional well-being (P = 0.04), and overall QOL scores (P < 0.01). The CONT group saw no significant changes in physical function or QOL. Effect sizes showed the WALK group had a larger positive effect on physical function and QOL. Minimal clinically important differences in the 6MWT and FACT-BMT were exceeded in the WALK group. CONCLUSION: A multidirectional walking program during the transplant period may be effective at increasing aerobic capacity and QOL for patients receiving HSCT compared with no structured exercise.