MicroRNAs are regulated by gene alteration, transcription, and processing. Thus far, few studies have simultaneously assessed all 3 levels of regulation. Using real-time quantitative polymerase chain reaction (QPCR)-based arrays, we determined changes in gene copy number, pre-miRNA, and mature miRNA levels for the largest set of primary effusion lymphomas (PELs) to date. We detected PEL-specific miRNA gene amplifications, and concordant changes in pre-miRNA and mature miRNA. We identified 68 PEL-specific miRNAs. This defines the miRNA signature of PEL and shows that transcriptional regulation of pre-miRNA as well as mature miRNA levels contribute nonredundant information that can be used for the classification of human tumors.