The objective was to study the pathogenesis of contact lens-associated giant papillary conjunctivitis (CL-GPC). Materials and Methods: Twenty-one biopsies of conjunctival giant papillae were obtained from soft contact lens wearers. The tissues were fixed in 4% paraformaldehyde and embedded in paraffin. Sections of 5 mum thickness were used for studies of histology and immunohistochemistry of pan-B and pan-T cell distributions. Results: Conjunctival epitheliums on the top of conjunctiva-associated lymphoid tissue typically lacked goblet cells. Lymphocytes from underlying lymphoid follicle were pressed into intra-epithelial 'pockets' formed through epithelial invagination. Under the follicle-associated epithelium, pan-B cells were mostly gathered in the central folliclar area and intraepithelial pockets, while CD3-positive T cells were predominantly distributed in parafolliclar region, but only a few in the intraepithelial pockets. Conclusions: Membranous epithelial cells (M cells) play a key role in the pathogenesis of CL-GPC for the binding and translocation of antigen and pathogen.