Clinical experience and in vitro investigations demonstrated that AlphaCor™, a hydrogel keratoprosthesis, can undergo both surface spoliation and internal depositions/colourations after exposure to certain medications, alone or in combination. While the most commonly used medications have not been associated with spoliation in vivo, many medications are reportedly used due to the complex co-pathologies in many recipients, and regional variations in available medications. We screened a number of drugs used or proposed by surgeons for use in AlphaCor patients to evaluate their potential to cause visually significant optic spoliation (surface or intragel, or colour changes). Poly(2-hydroxyethyl methacrylate) discs with an identical composition to AlphaCor's optic were incubated with each medication and then with simulated aqueous humour (SAH) at 37 °C for 7 days. They were then examined under magnification and by histology (selected samples). Clinical feedback for the test medications was reviewed and compared with the in vitro results. A minority of the drugs caused surface spoliation (TobraDex, Prednefrin Forte, Azopt) or colour staining (including Zymar, Vigamox, Quixin) when tested alone, but SAH appeared to promote hydrogel cloudiness and surface deposits. The in vitro spoliation occurred more frequently than in vivo reports of spoliation in recipients of the same medications. This study is consistent with earlier findings in demonstrating involvement of topical medications in hydrogel spoliation, although a much lower incidence of spoliation is reported for AlphaCor in human recipients than indicated by the laboratory findings. The interactions of biological fluids and drugs require further study.