One of the main toxicities associated to intravenous administration of amphiphilic drugs is pronounced hemolytic activity. To overcome this limitation, we investigated the anti-hemolytic properties of polymeric micelles of Pluronics, triblock copolymers of poly(ethylene oxide) and poly(propylene oxide). We studied the encapsulation of the amphiphilic compound miltefosine (HePC) into polymeric micelles of Pluronics F108, F68, F127, L44, and L64. In vitro hemolysis indicated that, among the five copolymers studied, only F127 completely inhibited hemolytic effect of HePC at 50 μg/mL, this effect was also observed for other two amphiphilic molecules (cetyltrimethylammonium bromide and cethylpyridinium chloride). To better understand this interaction, we analyzed the HC50 (concentration causing 50% of hemolysis) for HePC free and loaded into F127 micelles. Copolymer concentration influenced the hemolytic profile of encapsulated HePC; for F127 the HC50 increased relative to free HePC (40 μg/mL) up to 184, 441, 736 and 964 μg/mL, for 1, 3, 6 and 9% F127, respectively. Interestingly, a linear relationship was found between HC50-HePC and F127 concentration. At 3% of F127, it is possible to load up to 300 μg/mL of HePC with no hemolytic effect. By achieving this level of hemolysis protection, a promising application is on the view, bringing the parenteral use of HePC and other amphiphilic drugs. Additionally, small-angle X-ray scattering (SAXS) was used to asses structural information on the interactions between HePC and F127 micelles. Copyright © 2019 Elsevier B.V. All rights reserved.