The dramatic depopulation of honey bee colonies has not yet been associated to a single culprit, although many potential contributing factors have been identified. In an attempt to address the impact of an association of two factors on the honey bee, Apis mellifera, we studied the effects of a joint exposure to the microsporidian Nosema and the systemic insecticide imidacloprid, in the context of parasitisation by the mite Varroa destructor. Young adult bees were exposed to doses found in the field, in a lab rearing experiment. Survival, feeding behaviour, and specific activity of two immunity-related enzymes were investigated. Parasitisation by Nosema combined with sublethal intoxication to imidacloprid triggered energetic stress and mortality. The association of these two factors did not affect phenoloxidase specific activity, but decreased the activity of glucose oxidase. These results reveal a weakening of the jointly treated bees, suggesting that the depopulation phenomenon is likely to be triggered by multifactorial causes and that the two factors studied were amongst.