Hypoxia is damaging to normal cells as well as cancerous cells. Reports assessing hypoxia- and physioxia-induced global proteome changes in lymphoma are lacking. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to the acute hypoxic stress (1% of O2) and the physioxia (5% of O2) for a long-time. A total of 8239 proteins were identified by LC-MS/MS, of which 718, 513, and 486 have significant changes in abundance in Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant down-regulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, down-regulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of up-regulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a varia-ble oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL, potentially important in developing more aggressive phenotype.