The significance of cyclin D1 expression in plasma cell myeloma was examined by immunohistochemical analysis using a newly available rabbit monoclonal antibody with superior staining properties. Two patterns of positive staining were observed, each associated with distinct pathologic features. Strong cyclin D1 staining was associated with increased plasma cells at diagnosis (P=.026), lymphoplasmacytic morphologic features (P=.029), CD20 expression (P=.040), and t(11;14)(q13;q32) as detected by interphase fluorescence in situ hybridization with simultaneous CD138 immunofluorescence (P<.001). In contrast, weak staining was associated with hyperdiploidy (P=.02) and gains of the CCND1 locus (P=.01). Overall survival was longer in the cyclin D1+ cases than in cyclin D1- cases (estimated 3-year survival, 73% vs 27%; P=.005). Improved survival was seen in the strongly positive and weakly positive groups compared with cyclin D1- cases (P=.005). This report shows for the first time that cyclin D1 immunohistochemical analysis can provide prognostic information in plasma cell myeloma.