BackgroundDiffuse large B-cell lymphoma (DLBCL) is one of the most aggressive malignant tumors. Chromobox (CBX) family plays the role of oncogenes in various malignancies.MethodsThe transcriptional and protein levels of CBX family were confirmed by GEPIA, Oncomine, CCLE, and HPA database. Screening of co-expressed genes and gene function enrichment analysis were performed by GeneMANIA and DAVID 6.8. The prognostic value, immune cell infiltration and drug sensitivity analysis of CBX family in DLBCL were performed by Genomicscape, TIMER2.0, and GSCALite database. Confirmatory Tests of CBX family protein expression in DLBCL were performed by immunohistochemistry.ResultsThe mRNA and protein expressions of CBX1/2/3/5/6 were higher in DLBCL tissues than control groups. Enrichment analysis showed that the functions of CBX family were mainly related to chromatin remodeling, methylation-dependent protein binding, and VEGF signaling pathway. The high mRNA expressions of CBX2/3/5/6 were identified to be associated with short overall survival (OS) in DLBCL patients. Multivariate COX regression indicated that CBX3 was independent prognostic marker. Immune infiltration analysis revealed that the mRNA expressions of CBX family (especially CBX1, CBX5, and CBX6) in DLBCL were significantly correlated with the infiltration of most immune cells (including B cells, CD8 + T cells, CD4 + T cells, neutrophils, monocytes, macrophages, and Treg cells). Meanwhile, there was a strong correlation between the expression levels of CBX1/5/6 and surface markers of immune cells, such as the widely studied PVR-like protein receptor/ligand and PDL-1 immune checkpoint. Notably, our study found that DLBCL cells with CBX1 over-expression were resistant to the common anti-tumor drugs, but CBX2/5 had two polarities. Finally, we confirmed the higher expressions of CBX1/2/3/5/6 in DLBCL tissues compared with control groups by immunohistochemistry.ConclusionWe provided a detailed analysis of the relationship between the CBX family and the prognosis of DLBCL. Distinguished from other studies, We found that high mRNA expressions of CBX2/3/5/6 were associated with poor prognosis in DLBCL patients, and Multivariate COX regression indicated that CBX3 was independent prognostic marker. Besides, our study also found an association between the CBX family and anti-tumour drug resistance, and provided a relationship between CBX family expression and immune cell infiltration.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-11108-6.