Population-based studies analyzing clinical implications of nodal versus extranodal (EN) presentation of diffuse large B-cell lymphoma (DLBCL) are scarce. We studied clinical differences and trends in incidence, treatment and survival of nodal and EN DLBCL in a population-based cohort. All patients newly diagnosed with localized (Ann Arbor stage [AAS] I and II) nodal (n = 5124) and EN (n = 4776) DLBCL, and primary mediastinal B-cell lymphoma (PMBL; n = 88), diagnosed between 1989 and 2010, were selected from the Netherlands Cancer Registry. Primary EN disease was correlated with older age and more favorable clinical stage (AAS I). The age standardized incidence rates for men with localized EN DLBCL, and for men and women with localized PMBL, increased significantly, whereas the age standardized incidence rates of all other subgroups remained stable. The stomach was the most common EN localization. Patients with EN disease received less chemotherapy and targeted therapy than their nodal counterparts, irrespective of age and period of diagnosis. Their 5-year overall survival (OS) was 48% vs. 54% in the nodal group, but in multivariate analysis primary extranodal presentation was not independently associated with inferior survival. This population-based study shows clinically relevant differences between localized nodal and EN DLBCL and PMBL. Since patients with EN were significantly less often optimally treated, we advocate better interaction between medical disciplines.