Purpose: Ureteral stents are susceptible to biofilm formation and crystal deposition, especially in stone formers. To identify proteins responsible for this accumulation, we compared conditioning film proteomes obtained from human ureteral stents with and without encrustation. Materials and Methods: Twenty-seven Bard Inlay™ hydrophilic ureteral stents were removed after ureteroscopy. Stent encrustation was quantified by visual analog score 0 (none) to 4 (heavy) and further categorized as nonencrusted (scores 0 and 1; n=22) or encrusted (scores 2, 3, and 4; n=5). Stent conditioning film was sampled and digested with trypsin, and peptide tandem mass spectrometry data were acquired using liquid chromatography. After protein identification, unconditional exact tests were used to compare categorical variables versus encrustation outcome. Stone analysis and follow-up metabolic urine profiles were examined to identify additional risk factors for stent encrustation. Results: More than 300 unique proteins with >95% confidence were identified. Proteins α-1 anti-trypsin, Ig kappa, IgH G1, and histone H2b and H3a were found to be highly associated with stent encrustation (p<0.05), while Tamm-Horsfall protein and histone H2a were found to have a marginal association (p<0.1). Patients with early stent encrustation were more likely to have mixed stone analysis (p=0.03) and low urinary volumes (p<0.01). Conclusion: Immunoglobulins and Tamm-Horsfall protein are common urinary proteins that appear to nonselectively bind early onto ureteral stent surfaces. Histones, nuclear DNA-condensing proteins, likely contribute to stent encrustation because of their unique net positive charge and may represent a potential clinical target for encrustation prevention.