To determine a molecular mechanism for posterior vitreous detachment and contraction of vitreous gel, the effects of serum components on bovine vitreous were systematically studied. Incubation of vitreous gel with calf serum caused a contraction of the gel accompanied by the release of a waterlike liquid. The low molecular weight fraction (M(r) < 10,000) of serum was ineffective in this process, whereas incubation of the vitreous with the high molecular weight fraction resulted in changes in the gel structure similar to those caused by serum alone. Individually, transglutaminase (factor XIIIa) was found to be most effective in inducing gel contraction. The effect was more pronounced when transglutaminase was used with fibronectin. Since transglutaminase is known to promote collagen-collagen or collagen-fibronectin-collagen cross-links, the contraction of the vitreous in this case can be attributed to the formation of similar cross-links.