Three MAbs endowed with comparable affinity for 3 distinct epitopes of a HMW-MAA have been employed to study whether the use of combinations of MAbs might improve the sensitivity of methods for the quantitation of TAAs both on the cell surface and in soluble form. To this end, different combinations and sequences of application of the 3 MAbs were used both in cell-surface binding experiments and in solid-phase radioimmunoassays. Results of this study show that only selected combinations of MAbs are capable of significantly improving the sensitivity of methods for HMW-MAA detection, and that such improvements depend on the order and mode of addition of the 3 reagents. Thus, mixtures of MAbs to distinct epitopes carried by a single TAA molecule are likely to increase the sensitivity of tests for tumor detection both in vitro (i.e. radioimmunoassays) and in vivo (i.e. immunoscintigraphy). However, because the binding properties of such mixtures do not simply reflect those of the individual reagents, protocols for the use of MAb cocktails should be critically evaluated before clinical use.