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An important prognostic factor in patients with chronic lymphocytic leukemia (CLL) is the mutational status of immunoglobulin heavy chain variable region genes (IgVH), whose determination depends on the comparison between the nucleotide sequence of IgVH expressed by the leukemic clone of the patient and the germ line of the concerned family. If the calculated homology is >98%, the patient is deemed unmutated and the clinical course is unfavorable. Two reference database custodians of nucleotide sequences of the germ line [GenBank/IgBlast and Immunogenetics Information System (IMGT)] are the most accessed for the comparison. The aim of this work was to evaluate what database provides a more accurate assessment of the IgVH mutational status. The latter was examined by automated sequencing in patients with CLL (n = 204) and the percentage of homology was assessed by both databases. The analysis revealed that in six patients the two databases assigned a different family, because some alleles or families are present only in IgVH dataset of IMGT. When IgVH family was the same in both databases, the percentage of homology showed a difference in 50% of the subjects. Depending on the database used for comparison, six subjects, with homology close to 98%, have a different mutational status with associated different prognosis estimate. In conclusion, the IMGT database is more comprehensive and updated allowing to define the percentage of homology, and therefore the prognostic value, more accurately.