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Diffuse large B‐cell lymphoma (DLBCL) is the most frequent lymphoma. MIC‐A and MIC‐B are the natural ligands for NKG2D, a receptor expressed in NK cells. MIC‐A soluble isoforms (sMICA) have been described in different malignancies. Objectives: To analyze lymphocyte subsets and sMIC‐A in germinal center DLBCL. Materials and Methods: sMICA, sMICB, and peripheral blood lymphocyte subsets (CD4+, CD8+, NK, NKT, γδ T cells, and dendritic cells) were analyzed in 59 patients and 60 healthy donors. Results: Patients had decreased numbers of type 1 and type 2 dendritic cells, NK, iNKT, CD4 T, and CD8 T cells, and higher levels of sMIC‐A. The 2‐year PFS for high IPI scores and high sMIC‐A was 24% and 28%, respectively. The 2‐year OS for high IPI scores and high sMIC‐A was 42% and 33%. The 2‐year PFS and OS for patients not achieving response to treatment were 0% and 10%, respectively. The MICPI score (one point each for high IPI score and high sMIC‐A) showed that those patients summing two points had worse PSF and OS. Conclusions: Patients with DLBCL have decreased numbers of peripheral lymphocyte subsets and high levels of sMIC‐A. The addition of sMIC‐A to IPI could improve its prognostic relevance. [ABSTRACT FROM AUTHOR]