Radiation-induced trismus has a significant impact on the quality of life of patients receiving radiotherapy for head and neck cancers. Pentoxifylline has immunomodulatory activities that downregulate certain cytokines that have been implicated as mediators of fibrogenic reactions after radiation. A pilot study was therefore conducted to evaluate the efficacy of pentoxifylline in the treatment of radiation-induced trismus. Twenty patients with severe trismus (dental gap ≤ 25 mm) after receiving radiotherapy for nasopharyngeal carcinoma were enrolled onto the study. Four patients were excluded from analysis because of poor drug compliance. The remaining 16 evaluable patients completed an 8-week course of pentoxifylline at a dose of 400 mg two to three times daily. Changes in dental gap were recorded by measuring the distance between left upper and lower incisor before and after treatment. At the end of treatment, 10 patients had a measured increase in dental gap ranging from 2 to 25 mm. Six patients had an increment of 5 mm or more. The mean dental gap before treatment was 12.5 mm compared with 16.5 mm at the end of treatment (p = 0.023). The mean difference in dental gap was 4 mm, with a 95% confidence interval of 0.6 to 7.4 mm. The drug pentoxifylline appears to exert a modest therapeutic effect in patients with radiation-induced trismus, although our findings need to be confirmed by a randomized placebo-controlled study. While awaiting more evidence from clinical studies, a therapeutic trial of pentoxifylline is worth considering in patients experiencing radiation-induced trismus.