Background: Healthcare-associated infections (HAIs) represent a serious burden to individual safety and healthcare sustainability. Identifying which patients, procedures and settings are most at risk would offer a significant contribution to HAI management and prevention. The purpose of this study is to estimate 1) orthopaedic implantable device-related infection (OIDRI) prevalence in Italian hospitals and 2) the gap between the remuneration paid by the Italian healthcare system and the real costs sustained by Italian hospitals to treat these episodes. Methods: This is a cross-sectional study based on hospital discharge forms registered in 2012 and 2014. To address the first goal of this study, the national database was investigated to identify 1) surgical procedures associated with orthopaedic device implantation and 2) among them, which patient characteristics (age, sex), type of admission, and type of discharge were associated with a primary diagnosis of infection. To address the second goal, 1) each episode of infection was multiplied by the remuneration paid by the Italian healthcare system to the hospitals, based on the diagnosis-related group (DRG) system, and 2) the total days of hospitalization required to treat the same episodes were multiplied by the average daily cost of hospitalization, according to estimates from the Ministry of the Economy and Finance (MEF). Results: In 2014, 1.55% of the total hospitalizations for orthopaedic device implantation procedures were associated with a main diagnosis of infection, with a negligible increase of 0.04% compared with 2012. Hip and knee replacement revisions, male patients and patients older than 65 years were more exposed to infection. A total of 51.63% of patients were planned admissions to the hospital, 68.75% had an ordinary discharge to home, and 0.9% died. The remuneration paid by the healthcare system to the hospitals was € 37,519,084 in 2014, with 3 DRGs covering 70.6% of the total. The cost of the actual days of hospitalization to treat these episodes was 17.5 million more than the remuneration received. Conclusions: The OIDRI prevalence was lower than that described in recent surveys in acute care settings, although the numbers were likely underestimated. The cost of treatment varied significantly depending on the remuneration system adopted.