Background <p>According to the prevailing view among experts in the field of surgical research, homografts should be used preferentially over both conventional xenografts and mechanical prostheses in cases of infective endocarditis (IE). The rationale for this recommendation is that homografts possess a greater degree of resistance to infection. Nevertheless, the existence of comparative evidence that validates this assertion is scant.</p> Methods <p>A comprehensive search of the databases of three tertiary academic centres yielded a total of 775 adult patients (aged 18&#xa0;years or over) who underwent surgical procedures for active IE involving the heart valves during the period from 2005 to 2024. The evaluation of short- and long-term outcomes was conducted using propensity score analysis to reduce baseline confounding between patients receiving homografts and those receiving conventional prosthetic valves. Inverse probability of treatment weighting (IPTW) was applied to create weighted cohorts with balanced baseline characteristics.</p> Discussion <p>This study hypothesizes that the nature of the results in question will serve to minimize biases related to institutional volume and surgical experience in the case of homograft implantation when compared to conventional prosthetic valves. Participating centers must maintain an infective valve surgery program, with provisions to guarantee postoperative follow-up and management of late complications from valve surgeries for infective endocarditis. The data that will be collected will provide valuable insight into the comparative effectiveness of various surgical approaches, both standard and advanced, in valve replacement surgery for IE. This will be achieved using conventional prosthetic valves versus cryopreserved homograft. It is further expected that this comprehensive analysis will contribute significantly to the development of robust international guidelines.</p> Trial registration <p>Clinical Trial Gov. Com. ID: NCT05253469; IRB. ID: 2,022,011,054.</p>