Summary A few recent studies investigated the prognostic impact of CD30 expression in diffuse large B cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. No study has evaluated the significance of CD30 expression in DLBCL patients treated with rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH). In a group of 97 patients with DLBCL and high-risk features who received R-EPOCH induction therapy, we studied CD30 expression by immunohistochemistry using different cutoff values (> 0% and ≥20% of lymphoma cells, respectively) and correlated with prognosis. CD30 expression was detected in 24 (25%) cases using a cutoff of >0% and in 12 (12%) cases using a cutoff of ≥20%. The clinicopathologic features were similar between CD30+ and CD30-negative groups. A major difference was that MYC rearrangement was infrequent in the CD30+ group: 2/23 (9%) in CD30+ versus 25/72 (35%) in CD30-negative group (P = .02). CD30 expression was not associated with germinal center B-cell-like (GCB) or non-GCB type. Overall survival (OS) was not significantly different between patients with CD30+ versus CD30-negative DLBCL, either for all patients or the subset of patients without MYC rearrangement, regardless of cutoff (P > .05). CD30 expression was not associated with OS in either GCB or non-GCB subtype (P > .05, > 0% cutoff). In conclusion, CD30 expression was detected in up to 25% of cases of DLBCL and was more frequent in tumors without MYC rearrangement. CD30 expression was not associated with OS in R-EPOCH treated de novo DLBCL patients.