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Microplastic (MP) pollution is increasingly acknowledged as a critical environmental and public health issue. This study sought to establish a robust, clinically compatible method for detecting MP particles in deparaffinized formalin-fixed paraffin-embedded (FFPE) human colon tissue sections, using protocols compatible with routine clinical pathology. We employed mid-infrared photothermal (MIP) microscopy—also referred to as optical photothermal infrared (OPTIR) spectroscopy—as a non-destructive, high-resolution technique for chemical characterization and spatial mapping of polymer particles in intact FFPE samples. Following OPTIR analysis, identical sections underwent hematoxylin and eosin (H&E) staining to facilitate precise histopathological evaluation in defined regions of interest. Using this integrated workflow, we detected and localized polyethylene (PE), polystyrene (PS), and polyethylene terephthalate (PET) particles (21 PE particles, 1 PS particle, and 1 PET fiber) within distinct tissue areas. Subsequent histological assessment revealed characteristic inflammatory features near to these identified MP particles. To our knowledge, this represents the first demonstration of a diagnostic workflow that enables combined infrared spectroscopic and histopathological analysis of MPs in routinely processed human FFPE tissue. This approach offers a promising avenue to elucidate the role of microplastic accumulation in human disease and supports further investigation into potential mechanistic links between MP exposure and inflammatory processes in the colon.