A combination of two model approaches was used to explore the nature of silicone–protein interactions. Phage display technology was used to present a combinatorial library of peptides, in this case the phage library PhD.-12, to a series of model silicone surfaces. Solid, molecular cage silsesquioxanes were used as the models for silicone surfaces. The silsesquioxanes were octamethyloctasilsesquioxane (methyl⁸-T⁸), octaphenyloctasilsesquioxane (phenyl⁸-T⁸), octahydridooctasilsesquioxane (H⁸-T⁸) and dodecatrifluoropropyldodecasilsesquioxane (trifluoropropyl¹²-T¹²). The first two silsesquioxanes bear simple aliphatic (Me) and aromatic (Ph) pendant groups, and are simple silicone analogues. The second two silsesquioxanes have functionalised pendant groups, H and CF₃CH₂CH₂. The panning results, using a wild-type phage as a control, show that the phage library binds to the simple aliphatic and aromatic silsesquioxanes strongly but non-specifically, and largely through the protein coat on the phage. The functionalised silsesquioxanes (H and CF₃CH₂CH₂) are bound specifically by the phages. A statistical analysis of the DNA sequences of the strongly binding phages was carried out. The peptides that bind to H⁸-T⁸ are strongly enriched in proline content at positions 7 and 8, with enhanced histidine at positions 5 and 9, and enhanced threonine at position 11. The proline residues presumably induce a favourable conformation in the peptide for binding to the silsesquioxane surface. The enhanced histidine content is significant. It has been known for many years that imidazole has a particular affinity for electrophilic silanes. The amino acid distribution for trifluoropropyl¹²-T¹² binding peptides is markedly different from that of H⁸-T⁸ silsesquioxane. Proline is again enhanced, but in positions 4, 11 and 12, and there are also very high concentrations of serine in positions 1, 9 and 11, and threonine in positions 1, 2 and 12. The highly polar nature of the CF₃ group is likely to engage in hydrogen bonding with the OH groups of the serine and threonine side chains, accounting for the tight binding to trifluoropropyl¹²-T¹² silsesquioxane.