We analyzed specimens from 268 patients with small lymphocytic lymphoma (SL) to identify prognostic factors significant for survival. These patients were staged and treated according to the protocols of the Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, Southeastern Cancer Study Group, and the Southwest Oncology Group. Univariate analysis showed that a large-cell grade greater than I, WBC greater than 10,000/microL, hemoglobin (Hgb) less than 11 g/dL, age greater than or equal to 55 years, and failure to respond to treatment were all poor prognostic factors. Multivariate analysis showed that large-cell grade, age, degree of capsular invasion, and symptom type were independently associated with survival. Separate analyses of cases with and without leukocytosis indicated differences in survival. In patients without leukocytosis, age, presence or absence of anemia, and treatment response were significant prognostic variables; in patients with leukocytosis, large-cell grade, presence or absence of anemia, symptom type, and treatment response were significantly related to survival. Multivariate analysis showed that age was the only significant independent prognostic variable in patients without leukocytosis; in patients with leukocytosis, symptom type, large-cell grade, and bone marrow involvement were independently associated with survival. We conclude that several parameters, both clinical and pathologic, should be assessed at the initial diagnosis of SL to predict prognosis better.