Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein involved in the regulation of adipose tissue metabolism. However, its role in obesity and pregnancy is unknown. To evaluate the relationship between gestational weight gain (GWG) and circulating concentrations of ANGPTL4 in pregnant women with overweight and obesity, weight gain and fasting maternal blood samples of thirty-one pregnant women was drawn at 15, 24 and 32 weeks of gestation. ANGPTL4 concentrations continuously rose throughout gestation, whereas VEGF and leptin did not show the same trend. NEFA and glycerol concentrations remained stable during pregnancy. In contrast, total concentrations of saturated, monounsaturated and n-6 fatty acids, but not n-3 fatty acids, increased with pregnancy. In multiple regression analysis, the increase in plasma ANGPTL4 and decrease in linoleic acid concentrations were the most significant predictors of GWG, although only ANGPTL4 was significantly associated with the weight gain from early pregnancy (area under the ROC curve was 0.80 p < 0.01(95% CI 0.61–0.99)). In conclusion, in pregnant women with overweight and obesity, an increase in plasma ANGPTL4 concentrations throughout pregnancy is positively associated with GWG and could be used as an early marker of increased susceptibility to excess gestational weight gain.