Diagnostic criteria in myeloma have not been completely standardized or tested for accuracy; furthermore, marrow findings of prognostic value have not been clearly identified. We studied 176 patients with myeloma to determine the relative value of marrow differential, tissue sections, and immunohistology singly or in concert in the diagnosis of myeloma and to correlate morphologic features with prognosis. Controls were patients with benign marrow plasmacytosis. Homogeneous nodules of plasma cells at least 1/2 high-power field and/or monotypic aggregates of plasma cells filling at least one interfatty marrow space correctly identified myeloma in 83.5% of cases, with no false positives. The current numerical criteria of marrow plasmacytosis > or = 10% occurred in 17.1% of the controls, and 39.7% of patients with myeloma had less than 10% marrow plasmacytosis at presentation. Myeloma was graded histologically into categories of none/minimal, moderate, and marked dysplasia on the basis of dysplastic features and mitoses; these categories correlated well with clinical outcome, with median length of survival of 32.9, 25.2, and 12.9 months, respectively (overall median length of survival of 123 patients with myeloma, 29.2 months). Packing of marrow by tumor and mitoses measuring at least 5/high-power field regardless of grade also was associated with a poor prognosis (median lengths of survival, 15.2 and 11 months, respectively). Myeloma may be diagnosed in the great majority of cases by demonstrating homogeneous nodules and/or monotypic aggregates of plasma cells in the marrow. Prognostic features were shown to include marked dysplasia, mitoses, packing of marrow by tumor, and clinical stage.