Context- Macroprolactinemia is said to have no reproductive consequence, as the variant is biologically inactive and so, the patients may remain asymptomatic Objective - To find prevalence of macroprolactinemia and its association with reproductive dysfunction - Etiopathologic association of macroprolactinemia with autoimmune factors, heavy metal toxicity, bone mineral density and genetics factors Patients– 102 hyperprolactinemia patients (prolactin>100ng/ml in 2 occasions) included in study along with 24 controls and 135 physiological hyperprolactinemia (50 pregnant and 85 lactating) cases Methods– Polyethylene glycol precipitation done to segregate macro- from true hyperprolactinemia. Macroprolactinemia considered when prolactin recovery was <40% of initial prolactin value. To screen autoimmune basis IL 2, IL 4, IL 5 and IFN γ measured in serum by ELISA besides non-specific autoimmune markers (APTT, platelet, anti TPO, etc). Heavy metals chromium, cadmium, manganese and lead analyzed in serum using ICP AE spectrometry. Genomic screening for copy number variation studied using Illumina 300K bead array. Bone mineral density studied by DXAscan Main Outcome Measures– Prevalence of macroprolactinemia was 20.6% (21/102 cases). No macroprolactinemia detected in control individuals or physiological hyperprolactinemia cases Results– All macroprolactinemia cases presented with reproductive dysfunction (menstrual abnormality and infertility). No other associated cause of reproductive dysfunction observed in 52.4% cases (11/21). Incidence of thyroid disorders was 5 times less and renal disorders was 2.5 times less in macro- than in true hyperprolactinemia cases. IL 4 levels significantly higher in patients (p < 0.05) while chromium and manganese levels significantly low in patients (p < 0.05) in both macro- and true hyperprolactinemia groups. 66.67% hyperprolactinemia cases showed osteopenia/osteoporosis. No significant difference found in etiopathologic parameters between macro- and true hyperprolactinemia groups. Out of 22 CNVs (10 gains and 12 losses) revealed by DNA microarray, two were likely pathogenic and contained genes OLFML1 (11p15.4 loss) and HCCS (Xp22.2 gain) in pituitary microadenoma (with macroprolactinemia) and idiopathic hyperprolactinemia (without macroprolactinemia) cases respectively. Conclusion- Macroprolactinemia is frequently associated with reproductive dysfunctions. So, no clinical benefit in distinguishing macro- from true hyperprolactinemia.