The aim of this study was to prepare and evaluate buoyant lipospheres containing lercanidipine hydrochloride. The lipospheres were prepared by modified melt dispersion technique using hydrophobic matrix of cetostearyl alcohol (CSA). The influence of formulation factors (stirring speed, lipid:drug ratio, lipid:-surfactant polymer composition) on particle size, encapsulation efficiency and in-vitro release characteristics of lipospheres were investigated. The yields of all prepared formulation and encapsulation efficiencies were high for formulations which contain high lipid amount. The mean particle size significantly decreased (p < 0.001) by increasing the lipid:surfactant polymer and stirring speed (p < 0.001) of the system. Reduction in encapsulation efficiency (p < 0.001) and drug content (p < 0.001) was observed with increasing stirring speed and percentage of poloxamer 407 in formulation. Although lercanidipine hydrochloride release from Cetostearyl alcohol lipospheres were very slow and incomplete for all formulations f1-f6 (similar to 65% drug released in 12 h) and was increased (similar to 85% drug released in 12 h) in lipospheres formulations f7-f12, containing Poloxamer 407. Percentage of buoyant lercanidipine lipospheres of CSA (96-100% buoyancy up to 12 h) decreases (p < 0.001) with increasing percentage of poloxamer 407 and achieved the release profile suitable for peroral administration.