Splenic rupture may result in splenosis, the growth of splenic fragments. We used a parabiotic model to test the hypothesis that splenotic growth is governed by a circulating mediator(s). Pairs of C57B1/6 mice underwent side-to-side anastomosis. After 2 weeks, each of four groups underwent a second operation in which one or both of the partners had a sham operation or a splenectomy, or had splenic fragments transplanted into their peritoneums, or some combination thereof. Six weeks later, splenotic fragments were excised and weighed. Spleen fragments involuted when inserted into the pairs that had two intact spleens. In contrast, in pairs with one intact spleen and one set of fragments, multiple splenules developed, whose aggregate mass was approximately half (ratio, 0.53 +/- 0.04 [mean +/- SE]) that of the original transplanted fragments. Significantly more splenosis (P < .01) developed in pairs with no intact spleens and one set of fragments (0.82 +/- 0.04). The pairs with no intact spleens and twice as many fragments had an intermediate amount of splenosis (0.66 +/- 0.08). The authors conclude that (1) splenosis is inhibited by a factor (or factors) that circulates across the capillary network in a parabiotic pair of mice, and (2) the level of inhibition of splenosis appears to be directly proportional to total splenic mass. The authors speculate that spleen-saving operations, even if partial, may decrease the incidence of splenosis in the patient with a shattered spleen.