We introduce a sensitive method that allows one to distinguish positive and negative agglutination reactions used for blood typing and determination of Rh affinity with a high precision. The method is based on the unique properties of photonic crystal waveguides, i.e., microstructured waveguides (MSWs). The transmission spectrum of an MSW smart cuvette filled by a specific or nonspecific agglutinating serum depends on the scattering, refractive, and absorptive properties of the blood probe. This concept was proven in the course of a laboratory clinical study. The obtained ratio of the spectral-based discrimination parameter for positive and negative reactions () was found to be 16 for standard analysis and around 2 for used sera with a weak activity.