<b><i>Background:</i></b><i>SPROUTY2</i> (SPRY2) is a membrane-associated protein expressed by placental macrophages with regulatory roles in tissue growth and development. The <i>SPRY2</i> locus was shown to be associated with body fat distribution and susceptibility to type 2 diabetes. <b><i>Objectives:</i></b> We assessed whether <i>SPRY2</i> mRNA levels are related with maternal metabolic status and with placental weight. We also studied the association of placental mRNA of <i>SPRY2</i> with macrophage-derived inflammatory genes. <b><i>Methods:</i></b> A maternal metabolic profile [C-peptide, post-load glucose and high-molecular-weight (HMW) adiponectin] was assessed between 24 and 28 weeks of gestation in 200 control women delivering adequate-for-gestational-age (AGA) infants. Placentas and newborns were weighed at delivery. Placental mRNA levels of <i>SPRY2</i> and of macrophage-derived inflammatory genes <i>MMP2, TNFα </i>and <i>CD163</i> were quantified by real-time PCR. Women delivering small-for-gestational-age infants (SGA, n = 25) and women with gestational diabetes (GDM, n = 25) were also studied as validation groups for placental growth. <b><i>Results:</i></b> In control women delivering AGA infants, placental <i>SPRY2 </i>mRNA levels showed positive associations with a more adverse maternal metabolic status (higher maternal C-peptide and post-load glucose and lower HMW adiponectin), with more placental weight and with a more placental inflammatory phenotype (higher placental mRNA levels of <i>MMP2,</i><i>TNFα </i>and <i>CD163</i>) (all p < 0.05 to p = 0.001). Compared to AGA infants, placental weight and placental <i>SPRY2 </i>mRNA levels were lower in placentas from SGA infants and higher in placentas from women with GDM (all p < 0.0001). <b><i>Conclusions:</i></b> Our results suggest a link between placental <i>SPRY2</i> mRNA levels and placental growth, which may be modulated by maternal metabolic status and placental inflammation.