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In this work a new formulation of inhalable rifampicin-loaded PLGA microspheres (RIF-MS) is proposed for the management of tuberculosis treatment. For their formulation, the non-biodegradable polyvinyl alcohol surfactant was replaced with a biodegradable and biocompatible sucrose ester, sucrose palmitate. The effects of critical process and formulation parameters have been investigated and the obtained microspheres were characterized in terms of size, morphology, encapsulation efficiencies and RIF release profile. The optimized RIF-MS showed high drug loading (34.2%, w/w), an aerodynamic diameter compliant with deep lung delivery and an in vitro gradual and almost complete drug release over a week. The drug release data fitted well to the Higuchi models suggesting a drug release governed by Fickian diffusion. The RIF-MS uptake qualitative and quantitative studies on ex vivo rat alveolar macrophages (AM) revealed an efficient internalization of RIF-MS and their location in the perinuclear area. RIF intracellular levels were 7-fold higher in AM incubated with RIF-MS than with an equivalent amount of free RIF.