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Background: Diffuse large cell lymphoma (DLBCL) is heterogeneous in its clinical sequel. Approximately 50% of patients relapse after treatment and many succumb to the disease. Risk stratification of these patients is based mainly on the International Prognostic Index (IPI), while molecular profiling is not widely used for prognostication. Thus, there exists a need for identification of additional biomarkers that can be used as prognostic indicators for patients with DLBCL. Here we propose microRNAs, a family of small non-coding regulatory RNAs involved in cancer development, as an emerging class of potential biomarkers for risk stratification of DLBCL. Methods: Expression profiling of microRNAs was performed on RNA extracted from biopsy specimens of 83 DLBCL patients diagnosed and treated at Rabin Medical Center, using custom microRNAs microarrays. All patients were treated with CHOP or CHOP like therapy and were dichotomized into a “good prognosis” group (patients that achieved complete remission and no relapse within 5 years) and a “bad prognosis” group (patients that were either resistant to treatment or relapsed within 9 months). Expression levels were compared between the two groups of samples and statistically analyzed. The expression of differential microRNAs was verified using a microRNA qRT-PCR platform. Results: We found that several microRNAs are significantly differentially expressed in tumors from patients with bad prognosis compared with patients with good prognosis. Proprietary microRNA qRT-PCR showed a high correlation to microarrays and similar separation into prognosis groups based on miR expression. Conclusion: In summary, according to the results of this study, miRNA expression can serve as a novel tool for risk stratification and prognosis prediction of DLBCL patients. This approach can potentially be used to tailor treatment and further management to specific patient needs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4054.