Although the adipokine retinol-binding protein-4 (RBP4) has been implicated in the development of obesity-related insulin resistance, its role in human obesity is still unclear. Our objectives were to find out the effect on RBP4 systemic levels of a weight loss induced by gastric bypass surgery and to analyze RBP4 relationships with insulin resistance, parameters of body composition, lipid metabolism, and inflammation. Sixty-three obese women were analyzed before and 12 months after surgery of systemic concentrations of RBP4, fasting glucose, insulin, lipid profile molecules, and inflammation-related proteins (C-reactive protein, tumor necrosis factor-alpha receptors 1 and 2, interleukin-18, and adiponectin), and waist and hip circumference measurements, body mass index calculation, and insulin resistance index by homeostasis model assessment were also made. We found that RBP4 levels were lower after weight reduction by gastric bypass surgery (p < 0.0001). We found RBP4 associated with triglycerides before (beta = 0.37, p = 0.02) and after surgery (beta = 0.59, p < 0.0001) and negatively with weight loss after surgery (beta = -0.37, p = 0.003). When expressed as a percentage of change, the decrease of RBP4 was related to the reduction in the levels of triglycerides and with the increase in HDL-cholesterol (beta = 0.73, p = 0.02 and beta = 0.62, p = 0.04, respectively). Others parameters analyzed, including inflammatory markers, were not related to RBP4. This study shows that, in obese women and after a substantial weight loss due to bariatric surgery, RBP4 was related to weight status and lipid parameters rather than to insulin sensitivity or inflammatory markers.