The morphogenesis of cirrhotic septa in chronic hepatitis B was studied assuming that they arise at the sites of hepatocellular necrosis invoked by host immune reaction against HBcAg-expressing hepatocytes. Sections from three livers with chronic hepatitis B, all in cirrhotic stage, were immunostained with HBcAg and subjected to morphometry to analyze the distribution of HBcAg(+) hepatocytes and its relation with septa. HBcAg(+) cells were not distributed randomly over the nodules but forming focal areas. The septum formation along these foci was shown by 2-D distance distribution analysis, a technique we devised. Upon a sheet of color microphotograph of immunostained section, hundreds of test points each 400 μm apart were arranged by overlaying a tessellated grid. From each of the points hitting the nodules, the distance to the nearest nodulo-septal border D(min) was measured. Measurement was performed on a total of 2,585 test points. It was shown that the mean D(min) in the HBcAg(+) areas was significantly smaller than in HBcAg(−) areas. Thus, the cirrhotic septa are considered to arise at the places of HBcAg(+) foci, connecting them by postnecrotic collapsing.