Using normal human thyroid cells and tumor cells, the reconstruction of various diseased cells in collagen gel as well as the relationship between the morphology of colonies in collagen-embedded culture and the biological behavior (benignity, malignancy, metastasis, and invasion) of the original tumors were studied. In collagen gel culture, normal thyroid cells reorganized follicle-like constructions, and follicular adenoma cells showed in vivo-like constructions. However, two different types of colonies were observed in cultures of cells from papillary carcinomas. One was the branching type with many outgrowths projecting to three dimensions and the other was the spherical type without any outgrowths. These spherical colonies were observed in all cases of papillary carcinoma, but varied from one case to another. Metastasis and invasion were detected during pathological examination in cases with a high ratio of spherical colonies. Our results indicate that cells from highly metastatic and invasive thyroid cancer form spherical colonies in the collagen gel culture, and that this collagen culture is a useful method for studying the heterogeneity of tumor cells as well as the metastasis and invasive ability of tumor cells in vitro.