The most dreaded complication of familial Mediterranean fever (FMF) is amyloidosis; controversy exists as to what acute phase reactant (APR) should be monitored in these patients. To analyze the best acute phase reactant for FMF follow-up to help guide physicians to decide on what APR parameter to use, we also attempted to define the best APR in predicting the complications of FMF, specifically the development of amyloidosis. Systematic review based on a sensitive search to capture studies that: (1) included FMF patients; (2) measured serum amyloid A (SAA), CRP (C-reactive protein), proteinuria, or ESR (erythrocyte sedimentation rate); (3) amyloidosis were the outcome measure; (4) sensitivity, specificity, predictive value, and other performance parameters could be calculated; and (5) had a longitudinal design. Of 1905 captured items, 26 were selected for detailed review, of which only two finally met the criteria, and the quality was only moderate; the articles did not analyzed the performance by means of sensitivity and specificity to predict, or even detect, amyloidosis, and thus had to be calculated based on text. The 26 screened studies were very heterogeneous in designs, parameters measured, and results, despite being set from research questions similar to ours. They were mainly descriptive, and it was very difficult to interpret the true performance of the tests. The correlation between the various APR is low. The evidence supporting the monitoring of FMF with any APR over the others is limited. Well designed longitudinal studies with a mixture of outcomes should be undertaken. Until them, recommending an APR over other would be based on expert opinion and indirect evidence.