Cathepsin B-like cysteine protease (cbl) genes produce the most abundant mRNAs (16%) detected in the adult female intestine of the parasitic nematode Haemonchus contortus. CBL enzymes appear to digest host proteins and are vaccine candidates for immune control of H. contortus and potentially other parasitic nematodes. Hence, it is important to quantify the extent of diversity of H. contortus cbl genes. Here, expressed sequence tags (ESTs) were used to assess both the size and diversity of the H. contortus cbl gene family. Contig analysis of 686 cbl ESTs from a USA isolate resolved 123 clusters. ESTs were grouped into discrete sets and analyzed using an additive model. Discovery of new cbl clusters increased with each set and reached a terminal rate of about 1 per 10 ESTs. The extreme diversity was unique to cbls relative to other genes investigated and was ascribed to specific cbl clades. Sixty percent of cbl clusters from a UK isolate were shared with those identified in the USA isolate, suggesting conservation of cbl gene repertoires across regions, although minor to moderate geographic variation cannot be excluded. Sequence comparisons also suggested high potential for antigenic diversity among CBL proteins, which is relevant to vaccine strategies. Compared to other parasitic nematodes of mammals, the extreme abundance and diversity of intestinal cbl transcripts appear to be relative specializations for H. contortus. Therefore, adaptations related to nutrient acquisition may vary markedly among these parasitic nematodes.