Reticular networks in lymphoid organs play critical roles in the organization of local microenvironments. A number of these elements are maintained by continual signaling through the lymphotoxin system. Evaluation of the lymphotoxin (LT) pathway in primates using a fusion protein decoy provides a unique opportunity to assess modulation of splenic microenvironments in a species with considerably greater background immunological activity compared with rodents. Within the germinal center microenvironment, treatment resulted in a collapse of follicular dendritic cell (FDC) networks and in the disappearance of a ringlike network of immune complex–carrying cells, although some other attributes of the germinal center appeared to be unaltered. Treatment also resulted in changes in the splenic marginal zone, a microenvironment where the architecture is notably different from that of the rodent. Cessation of treatment and recovery allowed us to monitor reemergence of these cell types and revealed that FDCs rely on LT-dependent signals to recompact into appropriately positioned tight networks. Despite the loss of FDC networks, the primary Ab response to keyhole limpet hemocyanin was unaltered over a 20-day period. Manipulation of these microenvironments may represent a novel approach to modulating immune function in human disease.