In a color reproduction workflow, spectral prediction models are useful for establishing the correspondence between colorant sur- face coverages and resulting printed halftone color. Spectral predic- tion models enable calculation of the color gamut and establishment of the color separation tables. Discrete line juxtaposed halftoning, a recently proposed algorithm, is characterized by the fact that colorants formed by inks and ink superpositions are placed side by side. Juxtaposed halftoning is necessary when printing with special inks such as opaque or metallic inks. In order to predict the color of classical halftones, the Yule–Nielsen modified spectral Neugebauer model is generally used. However, this model may not predict the color of juxtaposed halftones, since the effective surface coverages of colorants and of possible colorant overlaps are unknown. In contrast, the two-by-two dot centering spectral prediction model developed by S. G. Wang enables the reflectance of slightly overlapping colorants to be captured and is therefore appropriate for predicting the color of juxtaposed halftones. Since this model requires a large calibration set, the authors use an estimation technique which predicts more than 90% of the two-by-two calibration pattern reflectances by measuring less than 10% of them. For juxtaposed halftoning, the two-by-two dot centering model offers high prediction accuracies and outperforms the different variants of the Yule–Nielsen spectral Neugebauer model for comparable setups.