Scion/rootstock interaction is important for plant development and for breeding programs. In this context, polyploid rootstocks presented several advantages, mainly in relation abiotic stresses. Here we analyzed the response to drought of two different scion/rootstock combinations presenting different polyploidy: the diploid (2x) and autotetraploid (4x) Rangpur lime rootstocks grafted with 2x Valencia Delta sweet orange scions (V/2xRL and V/4xRL). We developed an interactomic approach to identify proteins involved in V/2xRL and V/4xRL response to drought. A main interactomic network was built from V/2xRL and V/4xRL data. Exclusive proteins of the V/2xRL and V/4xRL networks, as well as common to both networks were identified. Functional clusters were obtained and two models of drought stress response were designed. Even if the V/2xRL plant implement some tolerance mechanisms, the global plant response to drought was rapid and quickly exhaustive resulting in a general tendency to dehydration avoidance, which presented some advantage in short and strong drought stress conditions. At the contrary, the V/4xRL plants presented a response which strong impacts on development but that present some advantages in case of prolonged drought. Finally, some specific central proteins were identified as good candidates for subsequent functional analysis of citrus genes related to drought response.