Considering that these potential diagnostic and prognostic targets may be regulated by events that do not imply variation in protein abundance levels, we investigated the hypothesis that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed LiP-MS in saliva samples to explore structural alterations comparing the proteome of healthy control and squamous cell carcinoma (OSCC) patients, with and without lymph node metastasis (N0 and N+, respectively). Our LiP strategy revealed 311 proteins with structural rearrangements when comparing among control and OSCC patients and 15 unique enriched biological processes, in contrast to 66 and 11 processes enriched in traditional proteomics workflow, mostly associated with immunity events. Moreover, 51 proteins with potential structural rearrangements were associated with clinical patient features, indicating conformotypic peptides associated with lymph node metastasis.