Electrospray ionization mass spectrometry (ESI-MS) investigations of noncovalently-bound complexes are of great interest because of their relevance to solution biochemistry. ESI-MS is particularly well suited to studies of weak interactions because it is very gentle and it allows studies to be performed under physiological or near-physiological solution conditions. However, it is not yet fully understood which weakly-bound complexes known to exist in solution will be observable by ESI-MS, or what minimum binding strength may be required for ESI-MS observation. Also unclear is whether complexes observed by ESI-MS reflect only species present in the bulk solution, or whether complexes also reflect aggregation in electrospray-generated microdroplets. We address some of these issues by employing ribonuclease S (RNase-S) as a test of the applicability of ESI-MS for analysis of noncovalent complexes. These results show that the ESI mass spectra of R Nase-S can reflect the specificity of binding in solution. 33 refs., 2 figs.