Abstract Background Skeletal involvement (SI) is observed at low prevalence in patients with diffuse large B-cell lymphoma (DLBCL). Due to the rareness of this particular condition, prospective trials for these patients are scarce. Methods We analyzed clinical characteristics and outcome of 75 patients with DLBCL and SI in order to identify factors with prognostic impact towards progression-free survival (PFS) and overall survival (OS). Results Limited stage disease (Ann Arbor stage IE-IIE) was present in 34 patients (45%), 41 patients (55%) had advanced stage disease (Ann Arbor stage IIIE-IVE). Outcome was generally favorable for patients with DLBCL and SI with 3-year OS of 83%. The international prognostic index (IPI) was able to distinguish between different risk groups within this specific entity. Additionally, hypercalcemia showed to be a factor significantly associated with inferior survival. In regard to first-line treatment modalities, consolidative radiotherapy was positively associated with prolonged PFS and OS while intensification of chemotherapy had no significant impact. Conclusions In our cohort of patients with DLBCL and SI, high-risk IPI as well as presence of hypercalcemia were associated with inferior outcome. Consolidative radiotherapy had a positive impact on survival.