Insertions/duplications and deletions (I/D/Ds) in IG variable region genes are infrequent sequelae of the somatic hypermutation process. In the present study, we document the occurrence of nucleotide I/D/Ds in rearranged IGHV genes in CLL patients. Among 809 IGHV-D-J sequences amplified in 760 CLL cases, 9 (1.11%) and 15 (1.85%) sequences exhibited IGHV sequence changes consistent with nucleotide insertions/duplications or deletions, respectively. I/D/Ds were found in genes of the IGHV1, IGHV3 and IGHV4 subgroups, always within mutated IGHV-D-J rearrangements. In 21/24 cases, the inserted/duplicated or lost nucleotides occurred in multiples of 3; therefore, the original reading frame was maintained and a potentially intact receptor was coded. I/D/Ds were located completely or in part within CDRs in 21/24 cases; sequence motifs (AGY, AGA, AAC trinucleotides) that resemble intrinsic hotspots for somatic hypermutation were identified in 21/24 sequences. Short stretches with high homology (misalignment feet) that would offer the DNA polymerase an alternative template for re-annealing in cases of replication slippage were identified in all CLL sequences carrying I/D/Ds. I/D/Ds were generated somatically since (i) they always occurred in cases with somatic mutations, (ii) they could not be found on sequencing analysis of the corresponding germline IGHV genes amplified on DNA isolated from selected patients’ neutrophils, thus excluding a possible genetic polymorphism. The incidence of I/D/Ds in CLL is consistent with previous reports in normal, autoreactive and neoplastic human B cells, thus seemingly indicating that these modifications generally arise without any particular disease-specific associations. A striking exception to this rule was identified in the case of CLL IGHV3-21 expressing cases: one aminoacid was deleted from the CDR2 region in 16/74 (21.6%) IGHV3-21 CLL sequences (database-derived IGHV3-21 CLL cases + present series) vs. only 2/340 (0.59%) non-CLL IGHV3-21 sequences; 15/16 CLL IGHV3-21 sequences carrying this deletion belonged to a subset with unique, shared HCDR3s and light chain CDR3 motifs. The effect of the CDR2 deletion on the structure of the IG molecules in this subset of CLL patients was studied with molecular modelling and dynamics simulations. The models suggested that the deletion could be accommodated without significantly affecting the local structure. The close association of deletions in CDR2 with the homologous subset of IGHV3-21 expressing CLL cases provides further evidence for the importance of an antigenic drive in malignant transformation and/or maintenance of the neoplastic clone in at least some CLL cases.