The aim of this study was to evaluate the clinical performance of adhesive filling materials in class V cavities in xerostomic head- and neck-irradiated cancer patients, in terms of marginal adaptation, anatomical form and recurrent caries. We selected 35 high-caries-risk, post-radiation, xerostomic adults with ≥3 cervical carious lesions in the same arch. Every patient received a KetacFil (KF), PhotacFil (PF) and Herculite XRV (HX) restoration. Patients were instructed to use a neutral 1% sodium fluoride gel in custom trays, on a daily basis. After 6, 12, 18 and 24 months, the restorations were examined for material loss, marginal integrity and recurrent caries. Fluoride compliance was determined at each recall appointment and recorded as the percentage of recommended use during that interval [compliance of ≤50% = NFUs, >50% = FUs]. Only 30 patients were available for recall at 6 months, with 28 patients at 12 and 18 months, and 27 patients at 24 months. In the NFU group, differences in recurrent caries were found between KF and HX at all observation times (p < 0.05). Differences (p < 0.05) in adaptation and/or anatomical form were found between KF and PF in NFUs after 18 and 24 months. In FUs, significant differences were observed between KF and PF, and KF and HX after 6 and 12 months, between KF and HX, PF and HX after 18 and 24 months. In summary, glass ionomers (especially the conventionally setting formulation) provide clinical caries inhibition but erode easily, while composite resin provides greater structural integrity.