Background and aim <p>There is limited evidence regarding the effect of demineralization around orthodontic brackets on shear bond strength (SBS). The aim of this in vitro fatigue study was to evaluate the effect of demineralization developing around orthodontic brackets bonded with different adhesive agents on fatigue-based SBS under laboratory conditions.</p> Methods <p>A total of 60 extracted human maxillary premolars bonded with Gemini metal brackets were randomly allocated into three groups (<i>n</i> = 20). Bracket bonding was performed using Transbond™ XT (acid etching + primer + adhesive) in Group 1, GC Ortho Connect^® (acid etching + one-step adhesive) in Group 2, and Transbond™ Plus (self-etch primer + adhesive) in Group 3. The mean demineralization values of the specimens were measured using a DIAGNOdent pen before demineralization (T0) and after 28 days of exposure to an artificial cariogenic environment (T1). Fatigue-based SBS was evaluated under cyclic loading (10&#xa0;N, 0.5&#xa0;Hz) at a crosshead speed of 300&#xa0;mm/min using a low-cycle fatigue testing machine and expressed as the number of shear strokes to failure. The level of statistical significance was set at <i>p</i> &lt; 0.05.</p> Results <p>There were no significant differences in demineralization values among the groups at either T0 or T1 (<i>p</i> &gt; 0.05). However, all groups showed a significant increase in demineralization at T1 compared with T0 (<i>p</i> &lt; 0.05). Group 2 (GC Ortho Connect^®) had a significantly higher number of shear strokes to failure than Groups 1 (Transbond™ XT) and 3 (Transbond™ Plus) (<i>p</i> &lt; 0.05). No significant difference was observed between Groups 1 and 3 (<i>p</i> &gt; 0.05). A significant negative correlation was observed between demineralization and shear strokes to failure across all groups (<i>p</i> &lt; 0.05). Hard tissue (enamel and dentin) damage occurred in nine specimens in Groups 1 and 3, and in seven specimens in Group 2.</p> Conclusions <p>Increased demineralization may negatively affect fatigue-based SBS and increase the risk of hard tissue damage. Under demineralized conditions, GC Ortho Connect^® may demonstrate more favorable fatigue-based bond performance compared with the other adhesive agents evaluated; however, further studies under clinically representative conditions are needed.</p>