This work describes the development and validation of a near infrared (NIR) spectroscopy method coupled with an appropriate multivariate calibration algorithm for the simultaneous quantification of encapsulated drug, simvastatin (SIM) and excipients, l-α-phosphatidylcholine (LPC) and cholesterol (CHO) in liposomes. The development of calibration models for each compound was based on a D-optimal experimental design consisting of 63 standard mixtures containing LPC, CHO and SIM in chloroform. For each compound, different spectral pretreatment methods were applied in association with selected spectral regions. Partial least-square regression (PLS) was performed using OPUS 6.5 software. Calibration set and cross-validation was carried out in order to select the best model to be used further. Straight line subtraction (SLS) was the best pre-treatment method for each compound, although the selected spectral regions were different. The method developed for each compound was validated in terms of linearity, trueness, precision and accuracy. Finally, the method has been successfully used for simultaneous quantification of SIM and excipients in liposomes. The encapsulation efficiency of SIM determined by this method was similar with that obtained by the use of reference HPLC method.