This study analyzes patients with head and neck diffuse large B cell lymphoma (HN-DLBCL), focusing on the differences in the biological characteristics and prognosis of lymphomas of nodal and extranodal origin. We have included 72 patients with stage I-II HN-DLBCL who had updated survival information and diagnostic paraffin-embedded tissue blocks available for review. Non-germinal center phenotype (73.7 vs. 32.4 %, P = 0.001) and high level of Bcl-2 expression (78.9 vs. 52.9 %, P = 0.025) were more frequent in nodal than extranodal lymphomas. Univariate analyses indicated that bulky disease, Ann Arbor stage II, high level of Ki-67 expression, and primary nodal disease had adverse effects on complete remission (CR), but these effects were confirmed in a multivariate analysis for primary nodal disease and bulky disease. Patients with primary extranodal lymphoma also had better overall survival (OS) (87.7 vs. 72.5 %, P = 0.04) and event-free survival (EFS) (84 vs. 58.5 %, P = 0.046) than patients with nodal disease, although in the multivariate analysis, only Ann Arbor stage II continued to predict worse OS and EFS, whereas bulky disease was an independent prognostic factor only for EFS. We found significant differences in the biological characteristics and prognosis between primary nodal and extranodal HN-DLBCL.