AbstractAcquired resistance to chemotherapy is an important clinical problem and can also occur without detectable cytogenetic aberrations or gene mutations. Chronic lymphocytic leukemia (CLL) is molecularly well characterized and has been elemental for establishing central paradigms in oncology. This prompted us to check whether specific epigenetic changes at the level of DNA methylation might underlie development of treatment resistance. We used Illumina Infinium HumanMethylation450 BeadChips to obtain DNA methylation profiles of 71 CLL patients with differential responses. Thirty-six patients were categorized as relapsed/refractory after treatment with fludarabine or bendamustine and 21 of them had genetic aberrations of TP53. The other 35 patients were untreated at the time of sampling and 15 of them had genetic aberration of TP53. Although we could not correlate chemoresistance with epigenetic changes, the patients were comprehensively characterized regarding relevant prognostic and molecular markers (e.g. IGHV mutation status, chromosome aberrations, TP53 mutation status, clinical parameters), which makes our dataset a unique and valuable resource that can be used by researchers to test alternative hypotheses.