Humoral memory to an antigen (Ag) is maintained for several decades in the form of memory B cells and serum Ab. In fact, plasma cells (PCs) that secrete Ab are known to be long-lived and could be solely responsible for maintaining the long-lived Ab titers. Alternatively, it has been proposed that the PC compartment is maintained for long periods by the differentiation of memory cells into long-lived PCs as a result of nonspecific stimulation. This model predicts accelerated decay of PC numbers in the absence of memory cells for the same Ag. To address this prediction, we have developed a mouse model system that combined the ability to deplete B cells with the ability to detect Ag-specific memory and PCs. After establishing an immune response, we depleted Ag-specific memory B cells with an anti-hCD20 mAb and determined the effect on the PC compartment over 16 weeks. Using a combination of surface markers, we demonstrated that memory B cells remained depleted over the course of the experiment. However, despite this absence of memory cells for an extended duration, PC numbers in spleen and bone marrow did not decline, which indicates that the PC compartment does not require a significant contribution from memory B cells for its maintenance and instead that PCs are sufficiently long-lived to maintain Ab titers over a long period without renewal. This observation settles an important controversy in B cell biology and has implications for the design of vaccines and for B cell depletion therapy in patients.