The mandatory R-Nano reporting system records between 300,000 and 400,000 metric tons of manufactured nanomaterials (NM) used annually within the country, potentially exposing a significant—though as yet undetermined—number of workers at sites where NM are produced and/or used. Indeed, for more than twenty years, these substances have been used in various sectors due to the specific and even innovative physicochemical properties conferred upon them by the nanoscale. However, these same characteristics also determine their behavior within the body and raise concerns regarding the risks these substances could potentially pose to human health, particularly that of workers who may be exposed to significant quantities. Due to concerns raised by the scientific literature, as part of its monitoring and alert missions as defined in the Public Health Code, Santé publique France was tasked in 2007 by the Directorate General for Health (DGS) and the Directorate General for Labor (DGT) to design and implement a national epidemiological surveillance system dedicated to workers potentially exposed to NMs. Following a feasibility study conducted in 2010, it was proposed to establish a prospective cohort study targeting workers exposed at production and/or use sites of four families of nanomaterials (titanium dioxide, silica, carbon black, and carbon nanotubes). This study aims to monitor potential health effects linked to occupational exposure to these nanomaterials, with a particular focus on respiratory and cardiovascular effects, while adopting a generalist approach. Indeed, given the uncertainties, the proposed method was intended to be pragmatic and adaptable. This protocol received approval from the DGS and the DGT. It entered the implementation phase under the name "EpiNano Program" in January 2014. Nevertheless, from the outset of its implementation in 2014, the EpiNano initiative faced deployment challenges, despite changes made following Phase 1 (2014–2016)—first through the revision of the communication strategy and streamlining of the questionnaires in 2017 (Phase 2), and then by implementing a systematic approach to soliciting target institutions, carried out during a pilot survey conducted in 2021–2022 among approximately fifty institutions and involving a polling service provider. In total, after ten years, only 26 private institutions with 630 workers were included. The limited data collected were analyzed for descriptive purposes. However, it should be noted that, given the limitations (selection/participation bias, job classification, small sample sizes, center effect, significant proportions of missing data, etc.), these results cannot under any circumstances be extrapolated to the entire population of establishments and workers affected by exposure to NMs. The results tend to reflect significant exposure levels as well as a partial lack of awareness among workers regarding their potential exposure to new materials, particularly regarding its intensity. Ultimately, field experience has shown, regardless of the recruitment phase (Phase 1 or 2 or pilot survey), there were difficulties in the process of recruiting facilities and collecting data, due in particular to the lack of regulatory incentives or mandatory tools necessary for a national epidemiological surveillance system, but also to the logistical challenges of such a study and the complexity of data collection. Consequently, these factors have led Santé publique France to discontinue the EpiNano system in its current form, as the methodology does not allow for the achievement of epidemiological surveillance objectives, primarily due to compromised feasibility for the reasons mentioned above.