Hyperprolactinemia has been found in a subset of systemic lupus erythematosus (SLE) patients. In order to explore whether antibodies to prolactin (PRL) play a role in SLE patients with associated hyperprolactinemia, we performed a cross-sectional study in which 259 consecutive SLE patients were tested for hyperprolactinemia and anti-prolactin autoantibodies. Forty-one (15.8%) had prolactin levels above the norm. The frequency of anti-PRL autoantibodies in hyperprolactinemia was 2/14 (14.3%). In the SLE patients with 'idiopathic hyperprolactinemia', 11/27 (40.7 %) had anti-PRL antibodies. The levels of serum PRL were significantly higher in patients with idiopathic hyperprolactinemia and anti-PRL autoantibody compared to the patients with idiopathic hyperprolactinemia who were anti-PRL autoantibody-negative. Patients with idiopathic hyperprolactinemia and anti-PRL autoantibody had relatively low SLE disease activity index (SLEDAI) scores and significantly different laboratory parameters compared to those with idiopathic hyperprolactinemia and no anti-PRL antibody. There was a significant correlation between titers of the anti-PRL autoantibody and serum PRL levels (rs = 0.98, P = 0.0001). These data suggest that anti-PRL antibodies could be the cause of hyperprolactinemia in a subset of SLE patients, especially those with particularly high serum prolactin levels with a diagnosis of 'idiopathic hyperprolactinemia'. The patients with anti-PRL antibody had fewer clinical manifestations and less serological activity, indicating that biological activity of PRL was attenuated by the autoantibody.