OBJECTIVE: To determine the optimal intra-articular iodine concentration for C-arm flat-panel computed tomography (FPCT) arthrography using advanced joint phantoms and to evaluate its application in human cadaveric wrists and elbows. Multi-detector (MD) CT served as the standard of reference. MATERIALS AND METHODS: Joint phantoms and 10 human cadaveric wrist and elbow joints were scanned with C-arm FPCT (5-s, 8-s, and 20-s runs) and standard MDCT using different and optimal concentrations of iodinated contrast material. CT numbers of contrast material, tissue, and noise were measured and contrast-to-noise ratios (CNR) calculated for quantitative analysis. Image and depiction of cartilage, bone, and soft tissues were rated. Radiation doses were compared. RESULTS: In FPCT, iodine concentrations positively correlated with CT numbers and noise of contrast material and with radiation dose (r = 0.713-0.996, p < 0.05 each). At an iodine concentration of 45 mg/ml, CNR of cartilage and soft tissues were highest for all FPCT acquisitions and higher than in MDCT. The 20-s FPCT run performed best for image quality and depiction of anatomical structures and was rated overall equal to MDCT (p = 0.857). CONCLUSION: The optimal iodine concentration for C-arm FPCT arthrography in this study is 45 mg/ml, leading to superior CNR and image quality for an optimal FPCT protocol compared with standard MDCT arthrography in human cadaveric joints.