Day 15 absolute lymphocyte count (ALC-15) after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) has been reported to be a significant predictor for survival in multiple hematologic malignancies. Limitations of previous reports included their retrospective nature and the lack of ALC-15 lymphocyte subset analyses. To address these limitations, from February 2002 until February 2007, 50 non-Hodgkin lymphoma (NHL) patients were enrolled in a prospective study. The primary endpoint of the study was to confirm prospectively the ALC-15 survival role after APHSCT in NHL. The secondary endpoint was to identify the ALC-15 lymphocyte subset affecting survival after APHSCT. With a median follow-up of 22.2 months (range: 6-63.7 months), patients with an ALC-15 > or =500 cells/microL (n = 35) experienced superior overall survival (OS) and progression-free survival (PFS) compared with those who did not; median OS: not reached versus 5.4 months, 3-year OS rates of 80% (95% confidence interval [CI]: 55%-95%) versus 37% (95% CI: 15%-65%), P < .0001; and median PFS: not reached versus 3.3 months, 3-year PFS rates of 63% (95% CI: 40%-85%) versus 13% (95% CI: 4%-40%), P < .0001, respectively. Univariately, CD16+/56+/CD3- natural killer (NK) cells were the only ALC-15 lymphocyte subset identified as a predictor for survival. Patients with an NK cell count > or =80 cells/microL (n = 38) experienced superior OS and PFS compared with those who did not (median OS: not reached versus 5 months, 3-year OS rates of 76% [95% CI: 57%-92%] versus 36% [95% CI: 11%-62%], P < .0001; and median PFS: not reached versus 3 months, 3-year PFS rates of 57% [95% CI: 38%-85%] versus 9% [95% CI: 1%-41%], P < .0001, respectively). Multivariate analysis showed that NK cells are an independent predictor for survival. This is the first study confirming the ALC-15 survival role prospectively and identifying NK cells as the key ALC-15 lymphocyte subset affecting survival after APHSCT.