Several gene expression profiles with a strong correlation with patient outcome have been previously described in chronic lymphocytic leukemia (CLL), although their applicability in clinical practice as biomarkers has been particularly limited. Here we describe the training and validation of a gene expression signature for predicting early progression of patients with CLL based on the analysis of 200 genes related to microenvironment signaling on the NanoString platform. In the training cohort (n=154), the CLL15 assay containing a 15-gene signature was associated with time to first treatment (TtFT) (HR: 2.83, 95%CI 2.17-3.68; p<0.001). The prognostic value of the CLL15 score (HR 1.71, [95%CI 1.15-2.52]; p=0.007) was further confirmed in an external independent validation cohort (n=112). Of note, the CLL15 score improved the prognostic capacity over the IGHV mutational status and the International Prognostic Score for asymptomatic early-stage (IPS-E) CLL. In multivariate analysis, the CLL15 score (HR: 1.83, 95%CI 1.32-2.56; p<0.001) and the IPS-E CLL (HR: 2.23, 95%CI 1.59-3.12; p<0.001) were independently associated with TtFT. The newly developed and validated CLL15 assay successfully translates previous gene signatures, such as the microenvironment signaling, into a new gene expression-based assay with prognostic implications in CLL.