The effect of [Vibrio cholerae] neuraminidase treatment on the antigenicity of sarcoma I (Sal) and mastocytoma P-815-X2 cells was compared in terms of their reaction with various antisera (C57BL/6 anti-Sal, C57BL/6 anti-mastocytoma, rabit and horse ALS[anti-lymphocyte scrum]) and complements (guinea pig, rabbit) or sensitized lymphocytes (C57BL/6 anti-SaI, C57BL/6 anti-mastocytoma, A anti-mastocytoma). With sensitized lymphocytes the reactivity of neuraminidase-treated tumor cells was similar to that of nontreated cells. After neuraminidase treatment, the tumor cells showed increased specific lysis with the antisera and complement. Rabbit complement was highly cytotoxic to the neuraminidase-treated cells but this nonspecific activity could be removed by absorption with agar or agarose. The results of this study would suggest that neuraminidase treatment does not change the antigenic determinants of tumor cells but increases their interaction with complement after removal of negatively charged sialic acids.