Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.