Simple SummaryThe standard treatment of patients affected by diffuse large B-cell lymphomas (DLBCLs) is represented by a chemoimmunotherapeutic regimen (R-CHOP) that is successful in about 60% of patients. Currently, we cannot know in advance if their disease will respond to R-CHOP. This study aimed at identifying predictive genetic biomarkers for R-CHOP response through the analysis of a very high number of host genetic polymorphisms. Of the 216 enrolled chemonaïve patients candidate to R-CHOP, 185 were eligible. Highly statistically significant associations were found between progression-free survival and six polymorphisms (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241), and between the overall survival (OS) and five polymorphisms (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569). Overall, wild-type patients (i.e., without these polymorphisms) showed prolonged survival compared with polymorphic patients. In the future, these polymorphisms, alone or in combination, after a proper validation in a further number of patients, could contribute to improving the prediction of R-CHOP response.AbstractR-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I–II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e.,p< 5 × 10−8) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles (p< 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response.