BACKGROUND Recent reports indicate the potential role of the stimulated by retinoic acid 6 (STRA6) protein in developing insulin resistance. The study's objective was to assess placental STRA6 expression and staining pattern in human pregnancy complicated by gestational diabetes mellitus (GDM). The expression pattern of further relevant genes involved in retinoid metabolism was also evaluated. METHODS A retrospective case-control study on paraffin-embedded placental tissue. Twenty-two human pregnancies affected by GDM, namely, 11 insulin-treated (iGDM) and 11 diet-controlled (dGDM), were compared with 22 normal-developed pregnancies (controls). An RT-PCR was performed in a random sample of 18 patients (six iGDM, six dGDM, and six controls) to assess RNA expression of STRA6 and further markers of retinoid metabolism. A semi-quantitative intensity evaluation at immunohistochemistry was performed for STRA6 in all 44 recruited patients. RESULTS STRA6 showed a decreased placental staining (9.09% vs. 68.18% positively stained samples, p < 0.05) and augmented RNA expression in dGDM patients than controls (ΔCT expression 0.473, IQR 0.403-0.566 vs. 0.149, IQR 0.092-0.276, p < 0.05). The protein staining pattern in patients affected by iGDM was comparable to controls. A reduced RNA expression of LPL, LRP1, VLDLR, and MTTP besides an augmented expression of LDLR was found in dGDM, while overexpression of LRP1 and LPL was found in iGDM patients. Unlike in the control group, significant positive correlations were found between RXRα and the proteins involved in the intracellular uptake of ROH, such as STRA6, LRP1, LRP2, and VLDLR. CONCLUSIONS An altered placental expression and staining pattern of STRA6 were found in pregnancies complicated by GDM compared to the controls. These changes were coupled to an altered expression pattern of several other genes involved in the retinoid metabolism.