Most cystic fibrosis (CF), results from deletion of a phenylalanine (F508) in the CF transmembrane-conductance regulator (CFTR, ABCC7) which causes ER-degradation of the mutant. Using stably CFTR-expressing BHK cell lines, we demonstrate that wild type- and F508delCFTR are cleaved into differently sized, N- and C-terminal bearing fragments, with each hemi-CFTR carrying its nearest nucleotide binding domain (NBD), reflecting differential cleavage through the central CFTR R-domain. Similar NBD1-bearing fragments are present in the natively expressing HBE epithelial cell line. We also observe multiple smaller fragments of different sizes in BHK cells, particularly after F508del-mutation (ladder pattern). Trapping wild type CFTR in the ER did not generate a F508del fragmentation fingerprint. Fragments change their size/pattern again post mutation at sites involved in CFTR's in vitro interaction with the pleiotropic protein kinase CK2 (S511A in NBD1). F508del- and S511A- mutation generate different fragmentation fingerprints that are each unlike wild type; yet both mutants generate a new N-terminal-bearing CFTR fragments that are not observed with other CK2-related mutations (S511D, S422A/D, T1471A/D). We conclude that F508delCFTR is not degraded completely and there exists a relationship between CFTR's fragmentation fingerprint and the CFTR sequence through putative CK2-interactive sites that lie near F508.