This study analyzed the frequency and clinical significance of t(4;14)(p16;q32) in multiple myeloma (MM) among 208 patients with MM and 52 patients with monoclonal gammopathy of undetermined significance (MGUS); diagnosed between 1994 and 2001. Patients with the translocation were identified using reverse transcription–polymerase chain reaction (RT-PCR) to detect hybrid immunoglobulin heavy chain (IgH)–MMSET transcripts from the der(4) chromosome. We found 31 (14.9%) t(4;14)⁺ MM patients and 1 (1.9%) t(4;14)⁺ MGUS patient. IgH-MMSET hybrid transcripts were detected in bone marrow (BM) and blood. Breakpoint analysis revealed that 67.7% of t(4;14)⁺ patients expressed hybrid transcripts potentially encoding full-length MMSET, whereas the remainder lacked one or more amino terminal exons. Expression of fibroblast growth factor receptor 3 (FGFR3), presumptively dysregulated on der(14), was detected by RT-PCR in only 23 of 31 (74%) patients with t(4;14)⁺ MM. Patients lacking FGFR3 expression also lacked detectable der(14) products. Longitudinal analysis of 53 MM patients with multiple BM and blood samples showed that, over time, BM from t(4;14)⁺ patients remained positive and that t(4;14)⁻ patients did not acquire the translocation. IgH-MMSET hybrid transcripts and FGFR3 transcripts disappeared from blood during response to therapy. No correlation was observed between the occurrence of t(4;14) and known prognostic indicators. However, we find the t(4;14) translocation predicts for poor survival (P = .006; median, 644 days vs 1288 days; hazard ratio [HR], 2.0), even in FGFR3 nonexpressors (P = .003). The presence of t(4;14) is also predictive of poor response to first-line chemotherapy (P = .05). These results indicate a significant clinical impact of the t(4;14) translocation in MM that is independent of FGFR3 expression.