The discovery of a strong association between hepatitis C virus(HCV) infection and mixed cryoglobulinemia(MC) has led to an increasingly rare diagnosis of idiopathic essential MC(EMC).The incidence of EMC is high in regions where there is a comparatively low HCV infection burden and low in areas of high infection prevalence,including HCV.The diagnosis of EMC requires an extensive laboratory investigation to exclude all possible causes of cryoglobulin formation.In addition,although cryoglobulin testing is simple,improper testing conditions will result in false negative results.Here,we present a 46-year-old female patient with a case of EMC with dermatological and renal manifestations,highlighting the importance of extensive investigation to reacha proper diagnosis.We review the need for appropriate laboratory testing,which is often neglected in clinical practice and which can result in false negative results.This review also emphasizes the significance of an extended testing repertoire necessary for better patient management.Despite a strong association of MC with HCV infection and other causes that lead to cryoglobulin formation,EMC remains a separate entity.Correct diagnosis requires proper temperature regulation during sample handling,as well as characterization and quantification of the cryoprecipitate.Inclusion of rheumatoid factor activity and complement levels in the cryoglobulin test-panel promotes better patient management and monitoring.Consensus guidelines should be developed and implemented for cryoglobulin detection and the diagnosis of cryoglobulinemic syndrome,which will reduce variability in inter-laboratory reporting. The discovery of a strong association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia (MC) has led to an increasingly rare diagnosis of idiopathic essential MC (EMC). The incidence of EMC is high in regions where there is a comparatively low HCV infection burden and low in areas of high infection prevalence, including HCV. The diagnosis of EMC requires an extensive laboratory investigation to exclude all possible causes of cryoglobulin formation. In addition, although cryoglobulin testing is simple, improper testing conditions will result in false negative results .Here, we present a 46-year-old female patient with a case of EMC with dermatological and renal manifestations, highlighting the importance of extensive investigation to reacha proper diagnosis. We review the need for appropriate laboratory testing, which is often neglected in clinical practice and which can result in false negative results. This review also emphasizes the significance of an extended testing repertoire necessary for better patient management. Desirable a strong association of MC with HCV infection and other causes that lead to cryoglobulin formation, EMC remains a separate entity. Correct diagnosis requires proper temperature regulation during sample handling, as well as characterization and quantification of the cryoprecipitate. Inclusion of rheumatoid factor activity and complement levels in the cryoglobulin test-panel promotes better patient management and monitoring. Consensus guidelines should developed and implemented for cryoglobulin detection and the diagnosis of cryoglobulinemic syndrome, which will reduce variability in inter-laboratory reporting.