We previously identified autoantibodies to the endocytic-associated protein Huntingtin interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (R-CHOP). HIP1R was preferentially expressed in germinal center-derived (GCB)-DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like (ABC-DLBCL) associated transcription factor, FOXP1. HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (10% tumoral positivity) significantly correlated with inferior overall (OS, P=0.0003) and progression-free (PFS, P=0.0148) survival in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray dataset, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.Leukemia accepted article preview online, 25 July 2013. doi:10.1038/leu.2013.224.