Very large prolactinomas are rare and may be difficult to treat. We present the report of a patient with an exceptionally aggressive tumour which extended outside the skull and emerged within the internal jugular vein. Bromocriptine induced only transient suppression of serum prolactin. In vitro studies of tissue from this prolactinoma showed that although prolactin secretion was reduced by both bromocriptine and dopamine, neither agent affected cytoplasmic levels of prolactin mRNA, suggesting relative autonomy of prolactin synthesis. We reviewed the progress of nine other patients with very large prolactinomas and serum prolactin levels greater than 100,000 mU/l. In three cases, treatment with bromocriptine rapidly reduced tumour size and serum prolactin levels became normal, but in the other cases responses were slower and less marked. Substantial amounts of residual pituitary tumour were seen in all cases where serum prolactin remained above 1000 mU/l, but also in one case where serum prolactin returned to normal, showing that serum prolactin levels are not reliable indicators of tumour size. Two patients died: one developed a CSF leak, and one pneumococcal meningitis in the absence of recognized CSF leakage. This emphasizes the significant morbidity associated with very large prolactinomas. The ideal long-term treatment of these tumours remains uncertain, but bromocriptine therapy alone is often inadequate. Cases of apparent bromocriptine resistance may reflect abnormal regulation of prolactin gene expression.