Human papillomavirus (HPV) does not induce lysis of infected keratinocytes, and the exact mechanisms of viral escape are not known. As keratinocytes differentiate, the cornified cell envelope (CCE) develops, providing a protective barrier to the host. Our prior studies have identified abnormalities in CCEs isolated from genital epithelium infected with HPV 11 (a low-risk HPV type) and HPV 59 (a high-risk HPV type). These abnormalities included reduced thickness and increased fragility compared to CCEs in healthy epithelium. Transcription of loricrin is also reduced in HPV 11- and 59-infected epithelium. In this study, uninfected and HPV 11- or 59-infected human genital epithelium were examined for expression of the small proline rich proteins (SPRs), which serve as cross-linking proteins within the CCE. Limiting cycle RT-PCR was performed to detect the various SPR transcripts in HPV 11- and 59-infected, or uninfected epithelium. Immunohistochemical analysis and immunoblot assays were performed to analyze the distribution and quantity of SPR2A, SPR2B, and SPR3. SPR2B transcripts were moderately increased in the HPV 11- and 59-infected tissues and SPR3 transcripts were significantly increased in HPV 11-infected tissues and minimally increased in HPV 59-infected tissues. SPR2B protein quantities were moderately increased while SPR2A was not significantly changed. SPR3 protein, while not present in uninfected epithelium, was detected in abundance in HPV 11-infected tissue. We conclude that low-risk and high-risk HPVs share the ability to alter expression of CCE proteins, although the exact mechanisms may differ. Expression of individual SPRs differed between these types and these alterations may play a role in fragility of CCEs in HPV infection.