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Stereotactic radiotherapy (SRT) using the Gill–Thomas–Cosman (GTC) repeat localizer allows for accurate and reproducible daily setup. The formation of a custom dental plate presents a challenge. We present the problems of utilizing this technique in patients with dentures. Twenty-seven patients were referred for fractionated SRT:15 patients had natural teeth and 12 patients had dentures. The comfort and accuracy of daily setup were compared in patients with and without dentures. All patients with natural teeth experienced no discomfort during the treatment and no interruptions were needed. The patients with dentures were categorized into four grades (I–IV), according to the need for medical intervention and necessity for treatment interruption. Two were Grade IV and SRT could not be delivered; alternate treatments were used (one had SRS and one had external RT). Three patients were Grade I, where there was minimal discomfort. Grade II discomfort was encountered in three patients helped by gingival anesthetic cream with no treatment interruption and Grade III was encountered in the remaining four where the treatment was interrupted for variable periods. The mean inaccuracy of daily setup was 2.1 ± 3.0 mm in patients with dentures and 0.48 ± 0.57 mm in patients with natural teeth. The use of the GTC frame is well tolerated and reproducible in patients with natural teeth. Variable degrees of discomfort are noted in patients with dentures and is well correlated to the degree of accuracy and reproducibility. Using other fixation devices, avoiding the oral cavity may be an alternative in patients with Grade III and IV discomfort.