The cross-reactive capacity of monoclonal and polyclonal lipid A antibodies was tested with rough and smooth lipopolysaccharides (LPS). The antibodies represented different specificities recognizing epitopes in the hydrophilic lipid A backbone. In none of the various assay systems applied did the antibodies react with complete rough or smooth-form LPS. Cross-reactions, in general, were only detected with the most rudimentary rough LPS tested, i.e. Re-LPS. A variety of reactivities with other LPS was shown not to be related to lipid A antibodies; such reactivities were present in rabbit sera as well as in crude ascites. These results underline the need for careful checks on the origin of reactivities observed. In addition, rabbit antisera raised with R- and S-LPS were screened for lipid A reactivity using synthetic lipid A and partial structures as antigens. No cross-reactivity of LPS antibodies with lipid A was detected in these sera.