Cryopreserved peripheral blood stem cell (PBSC) products can induce a number of infusion-related adverse reactions, including life-threatening cardiac, neurologic and other end-organ complications. Preliminary analyses suggested limiting the daily total nucleated cell dose infused might decrease the incidence of these adverse effects. A policy change implemented in December 2007, limiting the TNC dose to <1.63 × 109 TNC/kg/day, allowed us to assess the impact of this intervention on infusion-related safety, infusion schedules, engraftment and costs in cohorts of patients undergoing autologous stem cell transplants (ASCTs) two years before (325 ASCTs in 288 patients) and two years after the policy change (519 ASCTs in 479 patients). The percentage of autologous transplant patients requiring multiple day infusions increased from 6% to 24%. Concurrently, the incidence of infusion-related grade 3–5 SAEs decreased significantly, from 4% (13/325) pre-policy change to 0.6 % (3/519) post-policy change (p<0.0004). Multi-day infusions were not associated with increased time to neutrophil or platelet engraftment or the costs of transplantation. We conclude that limiting the daily TNC dose improved the safety of this procedure without compromising engraftment or increasing the costs of the procedure.