Despite significant technological advances, rheumatoid arthritis remains an incurable disease with great impact on the life quality of patients. We studied the encapsulation of tacrolimus in lipidcore nanocapsules (TAC-LNC) as a strategy to enhance its systemic anti-arthritic properties. TAC-LNC presented unimodal distribution of particles with z-average diameter of 212 +/- 11, drug content close to the theoretical value (0.80 mg mL(-1)), and 99.43% of encapsulation efficiency. An in vitro sustained release was determined for TAC-LNC with anomalous transport mechanism (n = 0.61). In vivo studies using an arthritis model induced by Complete Freund's Adjuvant demonstrated that the animals treated with TAC-LNC presented a significantly greater inhibition of paw oedema after intraperitoneal administration. Furthermore, the encapsulation of TAC in lipid-core nanocapsules was potentially able to prevent hyperglycemia in the animals. In conclusion, TAC-LNC was prepared with 100% yield of nanoscopic particles having satisfactory characteristics for systemic use. This formulation represents a promising strategy to the treatment of rheumatoid arthritis in the near future.