While diagnosing infection of a joint prosthesis often requires a multi-modal approach, evaluation of combined multiple diagnostics is still a rather subjective process. Based on the known sensitivity and specificity of commonly performed tests for joint prosthesis infection, we developed the Combined Diagnostic Tool, a software program that automatically allows the Combined Tests Index (CTI) to be calculated. The CTI indicates, in a given subject, the relative probability of a combined series of positive tests being true compared to negative tests. CTI values above 1 indicate a progressively higher chance of a prosthesis being infected and vice versa. Double-blind, prospective evaluation of CTI, compared to intra-operative cultural and histological findings, was performed in a consecutive cohort of 36 patients. 21 patients had positive intra-operative findings for infection. All of them had a pre-operative CTI >1 (range: 8.8 to 5552.6; mean: 711 +/- 1298). 15 patients had negative intra-operative results. All had a CTI <1 (range: 0.00013 - 0.297; mean 0.074 +/- 0.099). The difference in CTI between the two groups was statistically significant (p = 0.04). Our results show that the Combined Tests Index may be a useful indicator for differential diagnosis of prosthetic infection.