Adaptive natural killer (NK) cells are long-lived and exhibit properties of immunologic memory against cytomegalovirus (CMV). We previously reported that expansion of adaptive NK cells after CMV reactivation in recipients of allogeneic hematopoietic cell transplantation (HCT) was associated with a lower rate of relapse of acute myelogenous leukemia. In the present study, we examined the impact of adaptive NK cell expansion in a cohort of 110 individuals who underwent autologous HCT (AHCT) for a lymphoid malignancy (lymphoma or multiple myeloma [MM]). In this cohort, higher absolute numbers of adaptive NK cells (>1.58/μL) at day 28 post-AHCT were associated with significantly decreased risk of relapse in patients with MM. No significant association was seen in patients with lymphoma. Further stratification of MM patients by CMV serostatus found a strong protective effect of adaptive NK cells only in CMV-seropositive individuals. These findings suggest that strategies to increase adaptive NK cells after AHCT may be a therapeutic option in patients with MM.Keywords: Adaptive natural killer cells; Autologous transplant; Cytomegalovirus; Multiple myeloma.