The sequential changes of creatine kinase (CK) isoenzyme activity in serum and hamster buccal pouch tissue (HBPT) of normal, premalignant, and malignant stages during 13 wk of DMBA induced hamster buccal pouch squamous cell carcinogenesis, were studied. We found that the total CK activity in both serum and HBPT of the DMBA painted groups increased during the premalignant period (3-7 wk), with the peak being at 7 wk, while declining in the malignant period (9-13 wk). No significant difference in the serum and HBPT CK-MM, CK-MB and CK-BB activity, in DMBA-induced carcinogenesis, could be established. However, the macro CK type 2 (MCK-2), a cathodically migrating atypical creatine kinase isoenzyme, initially appeared in the sera and tissues of the 3rd wk DMBA-treated group. Its activity gradually increased during the premalignant and malignant stages, paralleling the increasing number of DMBA applications. There was a correlation between the degree of differentiation, and the size and number of the induced tumors with MCK-2. No MCK-2 could be detected in any of the sera or tissues of the control, nor in the 1st wk DMBA-treated group. We propose that MCK-2 is a potential tumor marker in oral malignancy and its presence may provide valuable information for early diagnosis of a possibly premalignant transforming oral lesion.