Background: Abnormal nuclear morphology associated with cancer may reflect changes in the proteins of the nuclear matrix. Methods: Nuclear matrix (NM) proteins were isolated from colonic tissue and analyzed by two-dimensional gel electrophoresis. Results: Several matrix proteins that were found in ulcerative colitis (UC) dysplasia (n = 5) and/or UC cancer (n = 4) were not identified in normal colonic tissue. UC dysplasia tissue showed three specific NM proteins with molecular masses of 49.2 kDa, 20.0 kDa, and 19.0 kDa, whereas 29.0-kDa and 32.0-kDa proteins were specific to UC cancer. Three proteins with 59.5-kDa (pI 6.3 and 6.6) and 33.75-kDa (pI 7.5) masses were common to both dysplasia and cancer tissue. Conclusions: These data suggest that NM proteins may have a role in the transition of tissue towards the malignant phenotype.