Mixtures of which the composition is not fully known are important in many fields of engineering and science, for example, in biotechnology. Owing to the lack of information on the composition, such mixtures cannot be described with common thermodynamic models. In the present work, a method is described with which this obstacle can be overcome for an important class of problems. The method enables the estimation of the activity coefficients of target components in poorly specified mixtures and is based on a combination of NMR spectroscopy with a thermodynamic group contribution method. It is therefore called the NEAT method (NMR spectroscopy for the Estimation of Activity coefficients of Target components in poorly specified mixtures). In NEAT, NMR spectroscopy is used to obtain information on the concentrations of chemical groups in the mixture. The elucidation of the speciation is not required, only the target component has to be known. Modified UNIFAC (Dortmund) is applied in the present work as group contribution method, but NEAT can be extended to any other group contribution method. NEAT was introduced recently by our group in a short communication, but only the basic ideas were presented. In the present work, NEAT is described in full detail. Different options of using NEAT are discussed, and examples for the application of the method are given. They include a variety of aqueous and nonaqueous mixtures. The results show very good agreement of the activity coefficients that are predicted by NEAT with the corresponding results for the fully specified mixtures.