Abstract Background We present a network-based method, namely quantitative proteomic signature profiling (qPSP) that improves the biological content of proteomic data by converting protein expressions into hit-rates in protein complexes. Results We demonstrate, using two clinical proteomics datasets, that qPSP produces robust discrimination between phenotype classes (e.g. normal vs. disease) and uncovers phenotype-relevant protein complexes. Regardless of acquisition paradigm, comparisons of qPSP against conventional methods (e.g. t-test or hypergeometric test) demonstrate that it produces more stable and consistent predictions, even at small sample size. We show that qPSP is theoretically robust to noise, and that this robustness to noise is also observable in practice. Comparative analysis of hit-rates and protein expressions in significant complexes reveals that hit-rates are a useful means of summarizing differential behavior in a complex-specific manner. Conclusions Given qPSPâ s ability to discriminate phenotype classes even at small sample sizes, high robustness to noise, and better summary statistics, it can be deployed towards analysis of highly heterogeneous clinical proteomics data. Reviewers This article was reviewed by Frank Eisenhaber and Sebastian Maurer-Stroh. Open peer review Reviewed by Frank Eisenhaber and Sebastian Maurer-Stroh.