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Early detection of melanoma metastases is essential for effective treatment and may be crucial for the prevention of systemic metastases and patient survival. However, data demonstrating the reliability and accuracy of ultrasound examination for the detection of lymph node metastases, in addition to clinical examination, are rare. We have examined 433 melanoma patients with stage-dependent follow-up intervals of 3 to 12 months. One thousand three hundred and thirty-two paired clinical and nonblinded sonographic tests of the locoregional lymph node areas were performed. Lesions suspicious of melanoma metastases were examined histopathologically. Of note, sensitivity 0.9394 (95 confidence interval: 0.7977–0.9926) and specificity 0.9808 (95 confidence interval: 0.9717–0.9875) of combined clinical and sonographic investigations were significantly (P<0.0001) higher than clinical results alone. Significant differences between clinical follow-up and sonographically assisted follow-up were found for American Joint Committee on Cancer 2002 melanoma stages I (P=0.0389), III (P=0.0101), and IV (P=0.0016). For stage II melanoma, a trend was detected (P=0.0821). Lymph node metastases were detected sonographically in 1.73 of clinically metastasis-free investigations (n=22). Our data suggest that high-frequency sonography should be part of all melanoma follow-up investigations, independent of melanoma type, melanoma stage, or lymph node biopsy status.