Ribonucleotide Reductase (RNR) converts ribonucleotides to deoxyribonucleotides required for DNA replication and repair. RNR consists of subunits M1 and M2. It has been studied as a prognostic factor in several solid tumors and in chronic hematological malignancies, but not in chronic lymphocytic leukemia (CLL). Peripheral blood samples were collected from 135 CLL patients. M1/M2 gene mRNA levels were measured and expressed as a RRM1-2/GAPDH ratio. M1 gene promoter methylation was studied in a patients’ subgroup. M1 mRNA expression was higher in patients without anemia (p =0.026), without lymphadenopathy (p =0.005) and 17p gene deletion (p =0.031). Abnormal LDH (p =0.022) and higher Rai stage (p =0.019) were associated with lower M1 mRNA levels. Higher M2 mRNA levels were found in patients without lymphadenopathy (p =.048), Rai stage 0 (p =0.025) and Trisomy 12 (p =0.025). The correlation between RNR subunits and clinic-biological characteristics in CLL patients demonstrate RNR’s potential role as a prognostic factor.