The association between hyperostosis frontalis interna (HFI), acromegaly and hyperprolactinaemia was investigated. Thirty six acromegalic patients, of whom 19 had hyperprolactinaemia, were compared with 36 randomly-selected, age-sex matched controls. There was a higher prevalence of HFI in the skull X-rays of the acromegalic cohort (P = 0.0002) when compared to the control group. This difference was apparent in both men (P = 0.01) and women (P = 0.01). Acromegalic patients with hyperprolactinaemia also expressed HFI in a higher proportion of individuals than the control group (P = 0.0001). Intra- and interobserver variability was assessed and concordance with 100% and 97% in the moderate and severe HFI sub-groups. The following sub-group analysis was undertaken: acromegalics and those acromegalics with hyperprolactinaemia were compared with the controls and a highly significant distinction was confirmed (P = 0.0007 and P = 0.00001 respectively). A relationship between HFI severity and the patient's age was noted in both male and female acromegalics. Also, the severity of HFI appeared related to disease duration in female acromegalics. The cause of HFI remains unknown but appears to be strongly associated with acromegaly, particularly in the presence of co-existent hyperprolactinaemia. The association may have symptomatic significance and the presence of HFI should be confirmed or refuted in all patients with acromegaly.