Objective To study the possible roles of P53, K-ras and hMSH2 genes in ulcerative colitis-associated colorectal cancers(UCACRC) and microsatellite instability (MSI) status during malignant transformation in ulcerative colitis (UC). Methods Immunohistochemical method was used to detect proteins of P53, K-ras and hMSH2 in paraffin-embedded tissues in 70 cases, including 25 cases of ulcerative colitis, 7 cases of ulcerative colitis with dysplasia, 8 cases of UCACRC and 30 cases of sporadic colorectal cancer(SCRC). The method of PCR-single strand conformation polymorphisms (PCR-SSCP) was used to detect MSI. Results The positive expressions of P53 and K-ras in UC with dysplasia or UCACRC were significantly higher than those in UC (P0.05 and P0.01 respectively). However, no significant difference was found between UC with dysplasia and UCACRC or between UCACRC and SCRC (P0.05). The rate of loss expression of hMSH2 in UC, UC with dysplasia, UCACRC and SCRC were not significantly different (P0.05). The positive rate of MSI in UC with dysplasia was significantly higher than that in UC (P0.01). However, no difference was found between UCACRC and UC with dysplasia (P0.05). The loss of hMSH2 protein expression was not found in UC with dysplasia and UCACRC. Conclusions Both the mutations of P53, K-ras genes and MSI are early events in UCACRC. There is no relationship between MSI and loss of hMSH2 protein expression in (UCACRC).