The polypeptide (p)50 molecule, a subunit of nuclear factor (NF)-κB, is produced after proteolytic processing of the p105 precursor (NF-κB1). Although the p105 precursor has been postulated to play a role in the regulation of the Rel/NF-κB activity, its physiological relevance remains unclear. To investigate that, we generated mutant mice lacking the COOH terminal half of the p105 precursor, but expressing the p50 product (p105−/−). These mutant mice displayed an inflammatory phenotype composed of lymphocytic infiltration in lungs and liver, and an increased susceptibility to opportunistic infections. Enlargement of multiple lymph nodes, splenomegaly due to erythrocytic extramedullary hematopoiesis, and lymphoid hyperplasia were also observed in p105−/− mice. Cytokine production in p105−/− macrophages was severely impaired, whereas proliferative responses of p105−/− B cells were increased. T cell functions were only moderately impaired in mutant mice. Loss of p105 also led to enhanced constitutive p50 homodimer and inducible NF-κB activities in unstimulated and stimulated cells, respectively. As several genes regulated by Rel/NF-κB were upregulated in p105−/− thymus but downregulated in p105−/− macrophages, the enhanced p50 homodimers appear to function as transcriptional activators or repressors, depending on the cell type. Thus, the p105 precursor is indispensable in the control of p50 activity, and lack of the precursor has distinct effects on different cells.