The migration of melanoma cells along the external surface of blood vessels (angiotropism) has recently been proposed as a mechanism for melanoma metastasis (termed extravascular migratory metastasis). To determine whether the presence of angiotropism, as seen in the routine hematoxylin and eosin sections of primary cutaneous melanomas (PCMs), predicts the development of local or in-transit melanoma recurrence, 32 patients with a PCM who developed local or in-transit recurrence were matched for Breslow thickness with 59 "control" patients with a PCM who did not. The slides from both groups of patients were analyzed in a "blinded" manner for evidence of angiotropism. Other histologic and clinical variables were also assessed. Angiotropism was found more often in patients who developed local or in-transit recurrence (cases) compared with those patients who did not (controls) (P=0.02). Variables that showed a statistically significant association with angiotropism on univariate analysis were: increasing Breslow thickness (P<0.0001), greater Clark level (P<0.001), increasing mitotic index (P<0.0001), presence of ulceration (P<0.01), and absence of regression (P<0.05). The median disease-free survival was 72 months for patients with angiotropism and 104 months for those without (P=0.02). On multivariate analysis the presence of angiotropism was an independent predictor of decreased disease-free survival (P=0.02). This is the first reported study to identify a statistically significant association between the development of local or in-transit recurrence of PCM and the histologic presence of angiotropism and that angiotropism is an independent predictor of decreased disease-free survival, as far as we are aware. Our findings support the hypothesis that angiotropism represents a pathogenic mechanism for metastasis in patients with PCM.