In the follow-up of melanoma patients, there is still a need for an optimal serum marker to discover recurrent disease at an early stage. Melanoma inhibitory activity (MIA) has been investigated as a serum marker for cutaneous melanomas. Although the prognosis for melanoma based on stage is generally good, the disease identified at later stages is associated with high levels of morbidity and mortality. The value of MIA testing in early-stage melanoma was the goal of this study. Five thousand three hundred and thirty-four MIA serum values from 1079 consecutive melanoma patients in stages I and II were obtained during routine follow-up at scheduled intervals. Sensitivity and specificity of MIA were calculated. The area under the receiver-operating characteristics curve and Somers' Dxy rank correlation were assessed. Metastasis occurred in 137 patients with a sensitivity of MIA testing of 67.6% in stage I and 65.6% in stage II patients. The specificity was 76.9% for stage I and 66.7% for stage II patients. The most reliable normal upper limit for MIA was redefined at 12.0 ng/ml, when compared with 8.8 and 15.0 ng/ml. Multivariate analysis revealed significantly more frequent false-positive values in elderly women and in men with an increased Breslow thickness.MIA adapted with a new cut-off level is then a useful serum marker even in the follow-up of not yet relapsed early-stage melanoma patients. In older women and in men with an increased tumor thickness, the higher rate of false-positive values should be considered before starting further diagnostics. Additional prospective studies to clarify the clinical combination with other serum markers seem promising.