Objective To evaluate endometrial BCL6 expression as a prognostic biomarker for In Vitro Fertilization (IVF) outcome in women with unexplained infertility (UI) prior to embryo transfer. Design Prospective cohort study. Setting University associated infertility clinic. Patients Women with UI for greater than 1 year. Interventions We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed mid-luteal phase biopsy and completed an IVF cycle and embryo transfer. Main Outcome Measure(s) Clinical pregnancy rate (CPR) and live birth rate (LBR) per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an HSCORE (> 1.4). Results Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher CPR (11/17; 64.7%; 95%CI: 41.3 to 82.6), compared to women with abnormal (high) BCL6 expression (9/52; 17.3%; 95%CI: 9.3 to 30.8). These results yield a relative risk (RR) of 0.267 (95%CI: 0.13 to 0.53; p = 0.0004) for those with normal BCL6 expression, an absolute benefit (AB) of 47.4% (95%CI: 22.5 to 72). LBR was also significantly higher in women with low BCL6 expression(10/17; 58.8; 95%CI: 36 to 78.4), compared to women with abnormal BCL6 expression (6/52; 11.5%; 95%CI: 5.4 to 23). The RR was 0.19 (95%CI: 0.08 to 0.45; p = 0.0002), yielding an AB of 47.3% (95%CI: 21.8 to 67.8). Conclusions Aberrant BCL6 expression (> 1.4 HSCORE) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI.