It has been shown that men who have sex with men actively seek lubricants that contain nonoxynol-9 (N-9) because they believe that N-9 may help to prevent infection by HIV. However, indirect evidence suggests that N-9 may actually enhance infection. Microscopic examination of rectal lavage and biopsy specimens collected at different time points following rectal application of a lubricant containing 2% N-9 showed rapid exfoliation of the rectal epithelium. Because the rectal epithelium protects target cells in the submucosa from HIV, we conclude that lubricants containing N-9 should be avoided during rectal sex.