Epigenetic modifications, such as DNA methylation, are crucial for both normal and tumor cell development. In chronic lymphocytic leukemia (CLL), multiple subsets have been reported that carry closely homologous, “stereotyped” B cell receptors (BCRs) with varying clinical outcome. To compare the methylation profiles of stereotyped CLL subsets, we here applied high-resolution methylation arrays (27,578 CpG sites) to 3 major subsets, i.e. poor-prognostic subsets #1 (IGHV1/5/7/IGKV1-39/1D-39, n=15) and #2 (IGHV3-21/IGLV3-21, n=9) and favorable-prognostic subset #4 (IGHV4-34/IGKV2-30, n=15). Overall, our results demonstrated significantly different and unique methylation profiles between these stereotyped subsets. Of particular interest was the observation that genes involved in apoptosis (e.g. RIPK3, AATK and TCF3) were methylated in subset #1 compared to subset #4, whilst genes involved in therapy resistance (e.g. ABCB11 and ITGAM) were unmethylated in subset #2 when compared to subset #4. Functional annotation of the differentially methylated genes revealed marked differences in genes involved in the adaptive immune response (e.g. CD80 and CD86), which generally remained unmethylated in subsets #2 and #4 in contrast to subset #1, indicating potential differences in antigenic response between subsets. Taken together, this data convincingly illustrates the distinct methylation profiles amongst stereotyped CLL cases and highlights a key role for epigenetics in disease pathogenesis.