Surfactant replacement significantly decreased acute pulmonary morbidity and mortality among preterm neonates with respiratory distress syndrome. Besides improving lung function and oxygenation, surfactant is also a key modulator of pulmonary innate and acquired immunity regulating lung inflammatory processes. In this review, we describe the immunomodulatory features of surfactant preparations. Various surfactant preparations decrease the proinflammatory cytokine and chemokine release, the oxidative burst activity, and the nitric oxide production in lung inflammatory cells such as alveolar neutrophils, monocytes and macrophages; they also affect lymphocyte proliferative response and immunoglobulin production, as well as natural killer and lymphokine-activated killer cell activity. In addition, surfactant preparations are involved in airway remodeling, as they decrease lung fibroblast proliferation capacity and the release of mediators involved in remodeling. Moreover, they increase cell transepithelial resistance and VEGF synthesis in lung epithelial cells. A number of different signaling pathways and molecules are involved in these processes. Because the inhibition of local immune response may decrease lung injury, surfactant therapeutic efficacy may be related not only to its biophysical characteristics but, at least in part, to its anti-inflammatory features and its effects on remodeling processes. However, further studies are required to identify which surfactant preparation ensures the highest anti-inflammatory activity, thereby potentially decreasing the inflammatory process underlying respiratory distress syndrome. In perspective, detailed characterization of these anti-inflammatory effects could help to improve the next generation of surfactant preparations.