In this study, the aim was to apply different comparison methods to dissolution profiles of immediate release commercial film-coated tablets of naproxen sodium in order to (1) evaluate each method in terms of easy application and usefulness and (2) identify the advantages and disadvantages of each method. Dissolution testing was conducted using the USP monograph of naproxen sodium. The applied methods for the comparison of in vitro dissolution profiles are ANOVA-based methods, model-dependent methods, and model-independent methods including difference factor, f(1), and similarity factor, f(2). All the methods appear to be applicable and useful in comparing dissolution profiles. The results show that ANOVA-based methods and model-dependent methods are more discriminative than the f-factors. f-Factors seem to be easier to apply and interpret; only one value is obtained to describe the closeness of the two dissolution profiles. However, a last point for dissolution had to be determined, since the values of the f-factors depend on this point. The application and evaluation of model-dependent methods are more complicated; these methods present an acceptable model approach to the true relationship between percent dissolved and time variables, including statistical assumptions which could be checked. Dissolution profiles can be tested for differences in both level and shape by ANOVA-based methods and these methods provide detailed information about dissolution data which can be useful also in formulation development to match release to a reference product.