Monoclonal B cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1-5%/year. Improved prediction of progression would greatly benefit individuals with MBL. CLL patients separate into three distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk IGLV3-21 rearrangements, impacting outcomes for these patients. Here we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for MBL individuals compared to other established prognostic indicators, including the CLL international prognostic index (c-statistic 0.767 versus 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL versus a cohort of 226 CLL patients revealed ELCLV3-21 high-risk MBL individuals had significantly shorter time to therapy (P=0.003) and reduced OS (P=0.03) compared to ELCLV3-21 low-risk CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.-