BACKGROUND The current study was conducted to analyze the outcome and prognostic factors of patients with diffuse large B‐cell lymphoma (DLCL) who did not achieve a complete response (CR) to first‐line treatment. METHODS The current study was comprised of 83 patients (43 males and 40 females with a median age of 62 years) who did not achieve a CR (58 of whom had primary refractory disease and 25 of whom achieved a partial response) with initial treatment (doxorubicin‐containing regimens in 87% of cases) from a series of 239 patients consecutively diagnosed with DLCL at a single institution. Initial variables, response to therapy, and salvage treatment were analyzed to predict survival. RESULTS Compared with patients who achieved a CR, nonresponders or partial responders more frequently were of advanced age and had a poor performance status (PS), B‐symptoms, advanced stage of disease, bone marrow infiltration, increased serum lactate dehydrogenase, and a high‐risk International Prognostic Index. Among the 58 patients with primary refractory disease, 18 died during initial treatment due to toxicity (14 patients) or disease progression (4 patients). The main variables predicting early death were a poor PS, age > 60 years, and an immunoblastic DLCL subtype. Twenty‐five of these 58 patients were able to receive salvage regimens, with only 1 of them achieving a CR. The median survival for this group of patients was 10 months. With regard to those patients achieving a partial response, 18 of the 25 patients received further therapy with 28% of them achieving a CR. The median survival was 23 months. The degree of the response was found to be the only significant variable with which to predict survival, with 2‐year survival rates of 4% and 40%, respectively, for patients with primary refractory disease and patients who achieved a partial response. CONCLUSIONS The prognosis of patients with primarily refractory DLCL is extremely unfavorable, whereas that of patients who achieve a partial response is slightly better. The inclusion of these patients in experimental trials is limited due to their tendency to be of an older age and to have a poor general status. Cancer 2001;91:1557–62. © 2001 American Cancer Society. The prognosis of patients with primary refractory diffuse large B‐cell lymphoma is extremely unfavorable, whereas that of patients who achieve a partial response to therapy is significantly better.