Abstract: The main challenges facing efforts to prevent the transmission of human immunodeficiency virus (HIV) are the lack of access to sexual education services and sexual violence against young women and girls. Vaginal formulations for the prevention of sexually transmitted infections are currently gaining importance in drug development. Vaginal mucoadhesive tablets can be developed by including natural polymers that have good binding capacity with mucosal tissues, such as chitosan or guar gum, semisynthetic polymers such as hydroxypropylmethyl cellulose, or synthetic polymers such as Eudragit® RS. This paper assesses the potential of chitosan for the development of sustained-release vaginal tablets of Tenofovir and compares it with different polymers. The parameters assessed were the permanence time of the bioadhesion—determined ex vivo using bovine vaginal mucosa as substrate—the drug release profiles from the formulation to the medium (simulated vaginal fluid), and swelling profiles in the same medium. Chitosan can be said to allow the manufacture of tablets that remain adhered to the vaginal mucosa and release the drug in a sustained way, with low toxicity and moderate swelling that ensures the comfort of the patient and may be useful for the prevention of sexual transmission of HIV.