Purpose We have previously reported on a polymeric micellar formulation of Cyclosporine A (CyA ) based on poly(ethylene oxide)- block -poly(ε-caprolactone) (PEO 5K - b -PCL 13K ) capable of changing drug biodistribution and pharmacokinetic profile following intravenous administration. The objective of the present study was to explore the potential of this formulation in changing the tissue distribution and pharmacokinetics of the encapsulated CyA following oral administration making comparisons with Sandimmune®. Methods The in vitro CyA release and stability CyA-loaded PEO- b -PCL micelles (CyA-micelles) were evaluated in biorelevant media. The pharmacokinetics and tissue distribution of orally administered CyA-micelles or Sandimmune® and tissue distribution of traceable Cyanine-5.5 (Cy5.5)-conjugated PEO- b -PCL micelles were then investigated in healthy rats. Results CyA-micelles showed around 60–70% CyA release in simulated intestinal and gastric fluids within 24 h, while Sandimmune® released its entire CyA content in the simulated intestinal fluid. CyA-micelles and Sandimmune® showed similar pharmacokinetics, but different tissue distribution profile in rats. In particular, the calculated AUC for CyA-micelles was higher in liver, comparable in heart, and lower in spleen, lungs, and kidneys when compared to that for Sandimmune®. Conclusions The results point to the influence of excipients in Sandimmune® on CyA disposition and more inert nature of PEO- b -PCL micelles in defining CyA biological interactions.