Intracellular replication of Salmonella enterica requires effector proteins translocated across the Salmonella-containing vacuolar membrane by Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). The SPI-2 T3SS effector SseL is a deubiquitinase that contributes to virulence in mice. Previous work has produced conflicting evidence as to the involvement of SseL in interference with the NF-κB pathway. To attempt to clarify these discrepancies, we compared mRNA levels in mouse primary bone marrow-derived macrophages infected with wild-type or sseL mutant strains using a genome-wide microarray. There was no detectable effect of loss of SseL on mRNA levels corresponding to any known NF-κB-regulated gene. In addition, there was no effect of SseL on (i) the activation or levels of both the canonical inhibitor of the NF-κB pathway (IκBα and phospho-IκBα), and the non-canonical NF-κB precursor p100/p52, (ii) the translocation of the NF-κB transcription factor p65 to the nucleus of infected macrophages and (iii) pro-inflammatory cytokines secretion. Furthermore, ectopic expression of SseL did not affect NF-κB activation in reporter cell lines. These results fail to support a role for SseL in the down-regulation of the host immune response and in particular the NF-κB pathway.