Inflammasomes are molecular complexes activated by infection and cellular stress, which are responsible for activating caspase-1 and subsequently facilitating interleukin (IL)-1β processing and macrophage cell death. The NLRP3 inflammasome is implicated in a growing number of human diseases and is activated by a wide range of infections and environmental stresses. The role of the AIM2 inflammasome in sensing cytosolic double stranded DNA (dsDNA) has been investigated using cell-lines and animal models but responses have not been clearly shown in primary human cells. As part of an ongoing investigation into the role of inflammasomes in autoimmunity we sought to optimise the experimental conditions required to measure inflammasome activation in primary human monocytes. We have developed techniques for measuring clear NLRP3 inflammasome responses including cell death and ASC-speck formation in human monocytes. In contrast, human monocytes had little or no AIM2 inflammasome response; chemically transfected dsDNA and other transfection complexes elicited IL-1b production that was inhibited by MCC950, a small molecule inhibitor of the NLRP3 inflammasome. Electroporated dsDNA had no discernable effect on the cells. This suggests that chemical transfection elicits an NLRP3 inflammasome response in a DNA-independent manner. This contrasts with mouse macrophages, where similar treatment activates the AIM2 inflammasome. This work provides important information for measurement of inflammasome responses in human cells particularly those expected to be mediated by AIM2.