Background <p>Complete dentures require periodic relining to compensate for progressive alveolar ridge resorption and associated loss of denture retention and stability. With the increasing adoption of digitally fabricated dentures using milling and 3D printing technologies, understanding the bond strength between these novel denture base materials and reline materials is essential for clinical success. This study evaluated the tensile bond strength of soft and hard reline materials bonded to denture base resins fabricated by three different manufacturing methods: conventional heat polymerization, milling, and 3D printing.</p> Methods <p>Ninety rectangular specimens were fabricated from three denture base materials: conventional heat-polymerized polymethyl methacrylate (PMMA) (Megacryl Hot), CAD-CAM milled PMMA (Voco Ceditec DB), and 3D-printed resin (Arma Resin). Specimens were divided into nine groups (<i>n</i> = 10) based on denture base material and reline material combinations. Three reline materials were tested: laboratory-processed silicone soft liner (Molloplast-B), chairside silicone soft liner (GC Reline II Soft), and chairside hard liner (Ufi Gel Hard C). All specimens were stored in distilled water at 37&#xa0;°C for 24&#xa0;h before testing. Tensile bond strength was measured using a universal testing machine at a crosshead speed of 5&#xa0;mm/min. Failure modes were classified as adhesive, cohesive, or mixed. Tensile bond strength was analyzed with a two-way ANOVA (denture base material × reline material) on log-transformed data after assumption testing (Shapiro–Wilk, Levene), with the Aligned Rank Transform applied as a non-parametric confirmation. Given a significant interaction, simple main effects were compared with Tukey-adjusted tests, and failure-mode distributions with the Fisher–Freeman–Halton exact test (α = 0.05).</p> Results <p>A significant denture base × reline material interaction was found (<i>p</i> &lt; 0.001), indicating that the effect of the denture base material on bond strength depended on the reline material used. The highest bond strength was achieved with Ufi Gel Hard C bonded to conventional PMMA (12.56 ± 2.21&#xa0;MPa), and the lowest with GC Reline II Soft bonded to 3D-printed resin (1.28 ± 0.16&#xa0;MPa). Differences among denture bases were reline-dependent: with the hard liner, conventional PMMA showed significantly higher bond strength than 3D-printed resin (<i>p</i> = 0.001); with Molloplast-B, all three denture bases were comparable; and with GC Reline II Soft, both PMMA bases outperformed 3D-printed resin (<i>p</i> &lt; 0.001). Adhesive failures predominated in 3D-printed groups (63.3%), whereas cohesive failures were most common in conventional PMMA groups (46.6%); Ufi Gel Hard C showed predominantly adhesive failures (83.3%), while GC Reline II Soft showed predominantly cohesive (56.7%) and mixed (43.3%) failures.</p> Conclusions <p>All tested combinations of denture base and reline materials demonstrated clinically acceptable bond strength, exceeding the minimum threshold of 0.44&#xa0;MPa established for soft denture liners. The hard chairside reline material exhibited superior bonding performance compared with both soft liners across all denture base types. The effect of denture base material was reline-material dependent: conventional PMMA demonstrated significantly higher bond strength than 3D-printed resin when combined with Ufi Gel Hard C, whereas both conventional and milled PMMA outperformed 3D-printed resin when combined with GC Reline II Soft. No significant differences among the denture base materials were observed with Molloplast-B. Although 3D-printed groups exhibited a higher overall incidence of adhesive failures, their bonding performance varied according to the reline material used. Clinicians should therefore consider the compatibility of each denture base–reline material combination, and further optimization of surface-treatment protocols may be beneficial for 3D-printed denture bases.</p>