Abstract Background: The reverse transcription-PCR tyrosinase assay (TYR test) cannot reliably detect malignant melanoma (MM) cells in blood as the cells often circulate at low concentrations. We evaluated the prognostic value of multiple TYR testing, the prognostic significance of individual positive TYR test results (TYR+) in asymptomatic melanoma patients, and whether statistical analysis could help in the interpretation of results of a test that measures phenomena that typically occur below its detection threshold. Methods: MM patients in stages I-IV (n = 150) underwent multiple testing with the TYR test during the course of their disease. TYR testing was performed as described by Smith et al. (Lancet 1991;38:1227–9). Statistical analyses were performed with the logistic function and t-test procedures. Results: The relationship between MM stage and the frequency of TYR+ was statistically significant (P = 0.011). Higher frequency of TYR+ in clinically asymptomatic patients after complete resection of the primary tumor was associated with an increased risk of recurrence of MM (prognostic sensitivity, 62%; specificity, 78%). Conclusions: A single positive TYR test provides a warning for disease relapse, suggesting that multiple TYR testing might provide more reliable predictions of disease progression. Multiple testing and statistical analysis using a logistic function might allow for the interpretation of apparently inconsistent results of tests for very rare cells.