It is estimated that as many as 70% of men who are HIV-positive have acquired HIV through unprotected vaginal sex; a much smaller proportion have acquired HIV through unprotected anal sex. So it is fair to say that the majority of men globally who have acquired HIV have done so through the penis.

An uncircumcised penis consists of the penile shaft, glans, urethral meatus, inner and outer surface of the foreskin, and the fraenulum, the thin band connecting the inner foreskin to the ventral aspect of the glans. A keratinised, stratified squamous epithelium covers the penile shaft and outer surface of the foreskin. This provides a protective barrier against HIV infection. In contrast, the inner mucosal surface of the foreskin is not keratinised and is rich in Langerhans' cells, making it particularly susceptible to HIV.

There is debate over whether the epithelium of the glans in men who are not circumcised is keratinised; some authors claim that it is not, but examination of the glans of seven circumcised and six uncircumcised men, and found the epithelia to be equally keratinised. In circumcised males only the distal penile urethra is lined with a mucosal epithelium. However, this is unlikely to be a common site of infection because it contains comparatively few Langerhans' cells.

It is well documented that ulcerative or inflammatory lesions of the penile urethra, foreskin, fraenulum, or glans that are caused by other sexually transmitted infections may provide additional potential routes for HIV transmission.