The present study was undertaken to investigate whether headache in women with nonpuerperal hyperprolactinemia was related to elevated serum prolactin (PRL) levels or the presence of a PRL-secreting pituitary adenoma. The subjects were 469 women seen initially during the period of 1973 to 1979 at four clinical centers with the complaints of secondary amenorrhea and/or galactorrhea, 212 of whom were subsequently diagnosed as having a prolactinoma. Headaches were four times more frequent (relative odds = 3.92; 95% confidence interval = 1.54 to 9.97) in the presence of an adenoma than in its absence. This effect was not altered by adjustment for PRL level or study center, nor could it be explained by confounding due to age, occupation, level of education, use of oral contraceptives, cigarette smoking, ethnic group, or history of head injury. Hyperprolactinemia was associated with headache only if a prolactinoma was present (chi 2 = 9.524; P = .002) and not in the absence of a prolactinoma (chi 2 = 1.547; P = .214). These findings suggest that the space-occupying mass effect of a prolactinoma is responsible for headache in women with nonpuerperal hyperprolactinemia. Despite its nonspecific nature, headache may be a useful indicator of the presence of an occult prolactinoma in women with secondary amenorrhea and/or galactorrhea.