This study addresses two hypotheses: (1) that the inherent potential of melanoma metastatic to regional nodal groups for lymph-mediated distant dissemination may not be the same for all nodal groups; and (2) that the risk of distant metastases in patients with clinically involved nodal metastases is higher than in patients with clinically occult nodal metastases. It involved a retrospective chart review of patients with histologically involved axillary or inguinal nodes treated at Roswell Park Cancer Institute (RPCI) (244 patients) or at the participating institutes from the Intergroup Surgical Trial (1ST) (108 patients). The distant recurrence rates of 623 melanomas with axillary or inguinal drainage from the 1ST data were also reviewed. In the RPCI data there was a significant difference in the overall and disease-free survival (P=0.0001) between patients with microscopic versus palpable involvement of the regional nodes in the axilla, while no such difference was observed for patients with groin metastases (P=0.30 and 0.36, respectively). The same trend was noted in the 1ST data. In the latter data the distant recurrence rate for melanomas drained via the axilla was significantly higher (P=0.026) than for those drained by the groin. In conclusion, lymphmediated distant dissemination may be more aggressive from the axilla than from the groin in melanoma.