BACKGROUND Although adding rituximab to the chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) has improved clinical outcomes of patients with diffuse large B-cell lymphoma (DLBCL), several recent studies have shown that the effect of rituximab is dominantly in the non-germinal center (non-GC) subtype compared to the germinal center (GC) subtype. Natural killer (NK) cell count, a surrogate marker of immune status, is associated with clinical outcomes in DLBCL patients in the rituximab era. We investigated whether the impact of NK cells on clinical outcomes differed according to the immunophenotype of DLBCL. METHODS This study analyzed 72 DLBCL patients treated with R-CHOP between January 2010 and January 2014. RESULTS Low NK cell counts (<100/µL) were associated with poor progression-free survival (PFS) and overall survival (OS) compared to high NK cell counts. In multivariate analysis, low NK cell count was an independent prognostic factor for PFS and OS. However, survival did not significantly differ between the GC and non-GC subtypes. We examined the clinical influence of NK cells according to the immunophenotype and found that low NK cell counts were significantly associated with poor PFS and OS in non-GC cases, but not in GC cases. CONCLUSION Low NK cell counts at diagnosis are associated with poor clinical outcomes in DLBCL patients treated with R-CHOP therapy. However, the impact is significant only in non-GC subtype DLBCL, not in the GC subtype.