In the new range, invasive species lack their specialist co-evolved natural enemies, which then might be used as biocontrol agents. Populations of both a plant invader in the introduced range and its potential biocontrol agents in the native range may be genetically differentiated among geographically distinct regions. This, in turn, is expected to affect the outcome of their interaction when brought together, and by this the efficacy of the control. It further raises the question, is the outcome of such interactions mainly driven by the genotype of the plant invader (some plant genotypes being more resistant/tolerant to most of the antagonist genotypes), or by the antagonist genotype (some antagonist genotypes being more effective against most of the plant genotypes)? This is important for biocontrol management, as only the latter is expected to result in more effective control, when introducing the right biocontrol agent genotypes. In a third scenario, where the outcome of the interaction is driven by a specific plant by antagonist genotype interactions, an effective control will need the introduction of carefully selected multiple antagonist genotypes. Here, we challenged in a complete factorial design 11 plant genotypes (mainly half-siblings) of the invasive Ambrosia artemisiifolia with larvae of eight genotypes (full-siblings) of the leaf beetle Ophraella communa, a potential biocontrol insect, and assessed larval and adult performance and leaf consumption as proxies of their expected impact on the efficacy of biological control. Both species were collected from several locations from their native (USA) and introduced ranges (Europe and China). In summary, we found O. communa genotype to be the main driver of this interaction, indicating the potential for at least short-term control efficacy when introducing the best beetle genotypes. Besides the importance of investigating the genetic structure both among and within populations of the plant invader and the biocontrol agent during the pre-release phase of a biocontrol program, we advocate integrating such bioassays, as this will give a first indication of the probability for an – at least – short- to mid-term efficacy when introducing a potential biocontrol agent, and on where to find the most efficient agent genotypes.