Oligodeoxynucleotides containing CpG motifs (CpG-ODN) represent potential adjuvants for specific immunotherapy of type I allergies because they foster Th1-like immune responses. However, previous work has shown that CpG-ODN induce systemically active levels of TNF-α in murine macrophages. The goal of the present study was to evaluate the release of TNF-α in human cells by a CpG-ODN proven to induce Th1 immune responses in cells from atopic individuals and in mice. CpG-ODN induced TNF-α in cells from atopic and healthy individuals. However, the amounts were low, as determined by comparison with commonly used Ags. Intracellular cytokine staining of PBMC revealed that CpG-ODN-induced TNF-α derived exclusively from B lymphocytes. TNF-α contributed to the CpG-ODN-augmented proliferation and Ig synthesis in PBMC, but was not involved in IFN-γ synthesis. In conclusion, our findings indicate that certain CpG-ODN induce low amounts of TNF-α in human B lymphocytes and may therefore be used to modulate Th2-biased immune responses in allergic patients.