Abstract In this work an innovative and low cost surface plasmon resonance (SPR) biosensor, based on the utilization of plastic optical fibers (POF), is presented and experimentally tested for the diagnosis and/or follow-up of celiac disease. In particular, the POF-based sensor was used to monitor the formation of the transglutaminase/anti-transglutaminase antibodies formation, a new hallmark for the diagnosis of celiac disease. In particular, on the gold layer surface of the POF sensor, the guinea pig transglutaminase was immobilized. The ability of the POF-sensor to detect the binding of anti-transglutaminase antibodies to the immobilized transglutaminase was studied. The obtained results showed that the POF-sensor is able to sense the transglutaminase/anti-transglutaminase complex in the range of concentrations between 30 nM and 3000 nM. Importantly, the proposed sensing method could be easily expanded to different target compounds.