Protamine sulfate given in high doses can inhibit angiogenesis in the granulation tissue generated in an open wound. This is reflected by changes consistent with delayed vascular maturation in the morphology of the regenerating vessels seen at the gross, microscopic, and ultrastructural levels. A coincidental delay in wound healing as evidenced by impaired wound contraction occurs, although fibroblast duplication and myofibroblast differentiation appear intact. However, the fibroblasts contain little endoplasmic reticulum, the site of synthetic activity, and the surrounding collagen appears loose and disorganized. To unite these observations into a coherent pattern, we review the proposal that the endothelial cell, the fibroblast, and the extracellular stroma are interdependent and that maturation of each is necessary to maintain the momentum of wound healing. Our findings fit this mechanistic hypothesis but do not prove it. The abnormal vasoformation that may be initiated by protamine's anticoagulant properties could set the stage for impaired fibroblast synthetic activity. If collagenous stroma is deficient, both endothelial maturation and wound contraction wound fail. Although we saw these final events, to prove a series of cause and effect changes would require further study of the oxygen tension and the fibrin and collagen levels in granulation tissue.