Portable Raman spectrometers may offer advantages for clinical medical diagnostics over laboratory instruments by allowing for quick measurements in the field and provision of data suitable for screening analyses. This work evaluates the potential of using available handheld, modular, and laboratory Raman spectrometers for screening normal colon tissues and benign and malignant colon polyps. The Raman spectra of tissue samples and reference biological macromolecules were measured with these instruments and analyzed using curve fitting and multivariate statistics. The spectra of calf thymus DNA measured with portable devices showed suitable signal-to-noise levels and half-widths of the prominent bands. Band positions, resolution, and relative intensities in the Raman spectra of colon tissues and reference compounds varied for the instruments, and the laboratory device demonstrated the best spectral feature. The principal component analysis (PCA) of the spectra obtained with all Raman devices showed well discrimination of normal colon tissue, adenomatous polyp, and adenocarcinoma. Dendrograms of similarity obtained using hierarchy cluster analysis (HCA) for the Raman spectra of all three devices also showed good separation of these samples. The soft independent modeling of class analogy (SIMCA) and support vector machine (SVM) models efficiently classified normal colon tissues and benign/malignant colorectal polyps based on the Raman data from all three devices. Despite its less pronounced spectral characteristics, the handheld Raman spectrometer can be used in early diagnosis of colorectal carcinoma, comparable to the modular and laboratory instruments.