Aspergillus fumigatus may cause infections in individuals with underlying lung damage, such as those with pulmonary tuberculosis (TB). Simultaneous exposure to A. fumigatus and Mycobacterium tuberculosis may worsen lung tissue damage, but the combined immune response to these pathogens has not yet been fully characterized. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with A. fumigatus conidia, M. tuberculosis H37Rv lysate, or both combined. TNF and IL-1β were measured from culture supernatants. The role of different pattern recognition receptors (PRRs) important for the recognition of both pathogens were explored by using PRR inhibitors and PBMCs from donors deficient in certain pathways. A. fumigatus and M. tuberculosis synergistically induced TNF and IL-1β release by PBMCs, and this response was independent of TLR2 and dectin-1. We found that the synergy is regulated through distinct intracellular pathways. The activation of the intracellular receptor NOD2 by M. tuberculosis and NADPH oxidase complex-dependent ROS production triggered by A. fumigatus mediate TNF but not IL-1β synergy. Together, these findings indicate that A. fumigatus and M. tuberculosis jointly exacerbate proinflammatory responses. This may help to explain the persistent inflammation and immunopathology observed in patients with concurrent TB and aspergillosis.