Macroprolactinemia is characterized by the predominance in the serum of macroprolactin, a prolactin (PRL) with high molecular mass and low biological activity that does not need treatment. The prevalence of macroprolactinemia was evaluated in 115 consecutive patients with hyperprolactinemia. Among them, 19 (16.5%) had solely macroprolactinemia, 4 (3.5%) polycystic ovary syndrome, 7 (6.1%) acromegaly, 8 (6.9%) idiopathic hyperprolactinemia, 10 (8.6%) primary hypothyroidism, 14 (12.2%) clinically non-functioning pituitary adenomas, 20 (17.4%) drug-induced hyperprolactinemia and 33 (28.7%) prolactinomas. The diagnosis of macroprolactinemia was established by the demonstration of a PRL recovery < 30% after treatment of sera with polyethylene glycol. Among the 19 patients with isolated macroprolactinemia, 16 (84.2%) were female and 12 (63.2%) were asymptomatic, while 4 (21%) presented with oligomenorrhea and 3 (15.8%) with galactorrhea. In contrast, only 11.5% of individuals with other causes of hyperprolactinemia were asymptomatic (p< 0.001). Prolactin levels in cases of macroprolactin ranged from 45.1 to 404 ng/mL (mean 113.3 +/- 94.5) but in 15 (78.9%) were < 100 ng/mL. Our findings demonstrate that macroprolactinemia is a common condition and, therefore, we suggest that it should be routinely screened in patients with hyperprolactinemia.