The value of tyrosinase messenger RNA (mRNA) detection by reverse-transcriptase polymerase chain reaction (RT-PCR) as a marker for circulating melanoma cells remains controversial. However, it has been suggested that detection of melanoma cell mRNA may be used to evaluate prognosis and disease progression in patients with advanced malignant melanoma. We used a highly sensitive tyrosinase RT-PCR detection assay to test peripheral blood specimens of 80 patients with metastatic malignant melanoma. Moreover, we developed a multiple marker RT-PCR assay detecting a variety of additional melanocyte/tumour specific markers addressing the potential heterogeneity of gene expression of circulating melanoma cells. Thus subgroups of 32 and 12 out of all the 80 patients were also analysed for multimarker gene expression in their peripheral blood and bone marrow specimens, respectively. Altogether, 15 out of 80 patients tested positive for one or more molecular markers with heterogeneous melanocyte/tumour gene expression patterns. All RT-PCR positive patients presented with progressive and widely disseminated disease. We concluded that the detection of melanoma cell mRNA occurs in a stage of massive tumour progression and may predict poor clinical outcome in advanced malignant melanoma patients (p < 0.001). In addition, the multiple marker RT-PCR analysis was more reliable and sensitive than a single molecular marker assay for the detection of melanoma cells.