Platinum compounds are the most effective drugs in the fight against ovarian cancer. Unfortunately, many ovarian tumors are not eradicated by chemotherapy due to the emergence of drug-resistant clones during therapy, and hence 5-year survival rate of women afflicted with this disease is just 18%. In the continued absence of an effective early detection test for ovarian cancer, there is a considerable need to develop treatment strategies that can either circumvent (e.g. gene therapy) or prevent the development of platinum resistance. A prerequisite for the development of such treatments is a detailed knowledge of factors that confer tumor cell resistance to platinum compounds. We have used surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS or SELDI) to identify low mass proteins that are uniquely expressed in ovarian tumor cells that are platinum-resistant. Only two polypeptide peaks (m/z 5041 and 7324) were consistently altered following the induction of cisplatin resistance in the OAW42 and 2780 cell lines. These peaks appear to be specific to cisplatin resistance as they are not altered in the same manner in a melphalan-resistant variant of OAW42. The exact identity of the polypeptide peaks is unknown, but appears to be unrelated to changes in several proteins that have been historically associated with cisplatin resistance. These data suggest that SELDI-based proteomic profiling may be useful in monitoring the emergence of cisplatin-resistant tumor cell clones.