Non-germinal center (non-GC) phenotype is an adverse prognostic factor in chemotherapy (CT)-treated diffuse large B-cell lymphoma (DLBCL) patients. To determine how high-dose therapy (HDT) supported with auto-SCT as first line therapy influences GC-associated outcome in young high-risk DLBCL patients GC and non-GC phenotypes were determined immunohistochemically from 63 patients. Of these, 29 primary high-risk DLBCL patients were treated with auto-SCT, whereas 34 CT-treated patients served as a control group. Consistent with previous studies, non-GC phenotype was associated with adverse outcome in CT-treated high-risk patients. In contrast, immunohistochemical classification by cell of origin did not associate with survival after auto-SCT. When the impact of treatment on the predictive value of cell of origin was analyzed, the non-GC patients, who received HDT, had a better failure-free survival (FFS) and overall survival (OS) than the patients treated with CT alone. In multivariate analyses, both age-adjusted International Prognostic Index (aaIPI) and treatment were independent prognostic factors for FFS and OS. For the patients with GC phenotype, the influence of auto-SCT on survival was not significant. The data imply that auto-SCT can overcome the adverse prognostic impact of the non-GC phenotype in patients with high-risk DLBCL and warrant additional prospective studies.