Objectives: To evaluate the effectiveness of isotretinoin for improving ¹³¹I uptake in recurrent/metastasized thyroid cancer with no/insufficient ¹³¹I uptake. Design: Retrospective analysis of 25 patients treated between June 1999 and May 2001. Methods: 15 female and 10 male patients were given isotretinoin at 1 mg/kg for 3 months, followed by ¹³¹I treatment. All patients received a ¹³¹I scan 72 h after administration, thyroglobulin measurement, chest X-ray and ultrasound of the neck, and some patients underwent a ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (n = 14) and computed tomography scan of the chest (n = 11). Results: In two out of 14 patients with raised thyroglobulin but no ¹³¹I uptake, a slightly improved ¹³¹I uptake was seen. In a further 11 patients an improvement of ¹³¹I uptake of known lesions was desired or further non-¹³¹I-accumulating lesions were known. A dosimetrically relevant improvement of uptake was seen in three of these patients. ¹⁸F-FDG uptake and thyroglobulin did not correlate with the success/failure of the isotretinoin treatment. Side effects including a strong 'sunburn', cheilitis, mucositis, conjunctivitis and raised transaminases occurred in two-thirds of patients. They were of an overall tolerable level and were reversible after isotretinoin had been stopped. Conclusion: From our clinical experience over a period of 2 years we conclude that the therapeutic effect of isotretinoin in thyroid cancer is certainly less than previously reported. An indiscriminate use of isotretinoin in all patients with otherwise untreatable thyroid cancer cannot be recommended.