The pathogenesis of perineural tumor invasion was studied by computer aided 3-D reconstruction of bile duct wall from two patients submitted to surgery for hepatohilar carcinoma, in order to analyze how and via what route carcinoma reaches the perineural spaces. Rabbits with VX2 carcinoma implanted in the wall of the common bile duct were also examined. It was found that carcinomas growing along the perineural spaces had abundant connections with the tumors growing outside the nerve, especially those lurking in the lymphatics. In an additional analysis on the wall tissues of bile duct from 35 patients operated for carcinoma, the degree of invasion into perineural spaces proved to correlate with that into lymphatics much higher than with venular invasion. Thus it is likely that tumors reach distant nerves mainly via lymphatics, i.e., forming satellite lymphogenous foci around nerves and then, as a second step, breaking into the perineural spaces.