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Quantum dots (QDs) are semiconductor nanocrystals extensively applied as optoelectronic devices, sensors and fluorescent probes for (bio)molecular species. Silver chalcogenides (i.e., sulfide, selenide and telluride) are examples of I–VI-based QDs, which have low toxicity and excellent colloidal stability and hold great promise for applications including photovoltaics, lighting and displays as well as biomedical imaging. In this study, we investigated the potential SEIRA effect of silver selenide QDs stabilized via mercaptosuccinic acid (Ag2Se–MSA QDs) in aqueous suspension for amplifying the IR signature of a variety of dye molecules. For this purpose, time-resolved attenuated total reflection (ATR) spectra were recorded after the deposition of aqueous dye vs. dye/QD solutions until total evaporation of the liquid at an Si ATR waveguide surface. As main results, experimental enhancement factors (EF) of up to 10.9 were obtained, which indicates that Ag2Se–MSA QDs are able to enhance IR signatures effectively. In addition, an approach based on principal component analysis (PCA) and Euclidian distances was introduced to determine a novel parameter termed the ‘multivariate enhancement factor’ (MEF), which may be more suitable for multivariate studies performed using design of experiments (DoE) to optimize the experimental conditions for SEIRA studies. These PCA studies also evidenced how the enhancement effect by Ag2Se–MSA QDs may indeed occur, and corroborate that chemometrics tools not only aid in data analysis, but may also improve the understanding and knowledge on SEIRA systems.