Peripheral blood absolute lymphocyte count (ALC) is a survival prognostic factor in hematological malignancies. No reports have addressed whether ALC at the time of first relapse (ALC-R) predicts survival. Thus, we assessed the prognostic significance of ALC-R in diffuse large B-cell lymphoma (DLBCL). Patients were required to have been diagnosed with first relapsed DLBCL, have ALC-R values, and to be followed at Mayo Clinic, Rochester. From Feb 1987 until March 2006, 97 first relapsed DLBCL patients qualified for the study. The overall survival (OS) and progression-free survival (PFS) were measured from the time of first relapse. The value of ALC-R >or= 1.0 x 10(9)/L was used for the analysis. Both groups (ALC-R >or= 1 or < 1 x 10(9)/L) were balanced for the international prognostic index at relapse (IPI-R) (P = 0.3), and for autologous stem cell transplantation (P = 0.4). Superior OS and PFS were observed with an ALC-R >or= 1.0 x 10(9)/L (N = 60) versus ALC-R < 1.0 x 10(9)/L (N = 37) [median OS: 28.7 months, 5 years OS rates of 39% versus median OS: 10.2 months, 5 years OS rates of 14%, P < 0.002; and median PFS: 14.8 months, 5 years PFS rates of 21% versus median PFS: 6.5 months, 5 years PFS rates of 8%, P < 0.004, respectively]. ALC-R was an independent prognostic factor for OS [RR = 0.4, P < 0.01] and PFS [RR = 0.5, P < 0.005]. ALC-R predicts survival suggesting that host immunity is an important variable predicting survival in first relapsed DLBCL.