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This chapter presents a comparative study among different colour models (RGB, HSI, CMYK, CIEL*a*b*, and HSD) applied to very large microscopic image analysis. Such analysis of different colour models is needed in order to carry out a successful detection and therefore a classification of different regions of interest (ROIs) within the image. This, in turn, allows both distinguishing possible ROIs and retrieving their proper colour for further ROI analysis. This analysis is not commonly done in many biomedical applications that deal with colour images. Other important aspect is the computational cost of the different processing algorithms according to the colour model. This work takes these aspects into consideration to choose the best colour model tailored to the microscopic stain and tissue type under consideration and to obtain a successful processing of the histological image.