Introduction: Silicon dioxide, produced as synthetic amorphous silica (SAS), is made of nanoparticles (NPs), either present as such or as agglomerates and aggregates, and is widely used in many types of food processes and products as an additive. To assess whether repeated, long-term exposure to SAS NPs may result in adverse effects, mice were exposed for 18 months via drinking water to NM-200, one of the reference nanostructured silica used for applications related to food, at 4.8 mg NM-200/kg body weight per day, a dose relevant to the estimated dietary exposure to SAS in humans. Methods: The experiment focused on the kidney and liver as target organs and was carried out in parallel using 3 mouse lines (wild type and transgenic) differing for the expression of a-synuclein, that is, murine and human mutated (A53T). Sensitive determination of silicon revealed higher contents in liver and kidneys of NM-200–exposed mice compared with unexposed aged-matched controls. Results: Histological abnormalities, such as vacuolization of tubular epithelial cells, were detected in all kidneys, as well as inflammatory responses that were also detected in livers of exposed animals. Less frequent but more deleterious, amyloidosis lesions were observed in glomeruli, associated with perivascular amyloid accumulation in liver. Conclusion: These histological findings, in conjunction with the observation of detectable deposition of silica, highlight that chronic oral intake of SAS may pose a health risk to humans and need to be examined further.