Polymerase chain reaction is widely used in clinical practice as a reliable assay for the detection and quantitation of hepatitis C virus RNA in serum and tissue. Due to the high sensitivity of the test, both false positive and false negative results can occur. The presence of cryoglobulins in serum samples represents a variable that can influence the result of a polymerase chain reaction assay leading to false negative results. In cases of hepatitis C virus infection associated with cryoglobulinaemia, it is extremely important to very carefully process the samples to be tested in order to avoid cryoglobulin precipitation and the consequent removal of the virus from the sample.