Purpose: To assess the efficacy of two experimental denture adhesive gels (adhesives 1 and 2) compared to a commercially available denture adhesive cream (positive control) and no adhesive (negative control). Materials and Methods: This was a single-center, randomized, four-treatment, examiner-blind, crossover study in participants with well-made and at least moderately well-fitting maxillary complete dentures. Incisal bite force until denture dislodgment was measured before application (baseline) and over the following 12 hours for each of the treatments. Between-treatment differences in the area over baseline (AOB) for the bite force at each time point were analyzed using an analysis of covariance model. Results: The efficacy and safety analyses were based on results from 48 participants. Compared to the negative control, adhesive 1 showed a statistically significantly higher bite force AOB over 12 hours (AOB_0-12h; primary endpoint), as well as for AOB_0-6h and AOB_0-9h (all P .05), but not for AOB_0-1h or AOB_0-3h. Adhesive 2 was not significantly different from the negative control or from adhesive 1 for any measure of AOB. The positive control was associated with a significantly higher bite force AOB than either of the experimental adhesives for all time points (P .05). Although the positive control was well tolerated, both experimental adhesives were associated with a larger number of oral adverse events. Conclusion: Only adhesive 1 was significantly better than the negative control, and its performance did not match that of the positive control. Adhesives 1 and 2 showed the largest number of oral adverse events.