Rheumatoid arthritis and osteoarthritis can be treated through specific drug injection into the intra-articular space. Several failures during drug injection attempts with conventional fluoroscopy and ultrasonography in a small area of the intra-articular space have been reported. In this work we present an innovative impedance measurement-based method/algorithm for needle tip positioning to enhance image-guided intra-articular vaccination treatment. A novel algorithm for detecting the intra-articular space in the elbow and knee joints of a live porcine model is reported. An impedance measurement system was developed for biological tissue measurement. The electrical impedance in the intra-articular space was monitored and the needle tip was examined by ultrasonography. The contrast dye was vaccinated and checked using fluoroscopy to confirm that the dye was properly inoculated in the cavity. The electrical impedance was estimated for various needle inclusion profundity levels in saline solution, which were broadly used to evaluate the proposed device for in vivo examinations. Good efficiency was observed in the impedance-based measurements using a monopolar injection needle for intra-articular therapy. To enhance the needle tip positioning for intra-articular therapy, the intended impedance measurement device with a monopolar injection needle can be used as a complement to existing modalities.