Responses of the Medicago truncatula-Sinorhizobium interaction to variation in N2-fixation of the bacterial partner were investigated. Split-root systems were used to discriminate between local responses, at the site of interaction with bacteria, and systemic responses related to the whole plant N status. The lack of N acquisition by a half-root system nodulated with a nonfixing rhizobium triggers a compensatory response enabling the other half-root system nodulated with N2-fixing partners to compensate the local N limitation.This response is mediated by a stimulation of nodule development (number and size) and involves a systemic signaling mechanism related to the plant N demand. In roots co-infected with poorly and highly efficient strains, partner choice for nodule formation was not modulated by the plant N status. However, the plant N demand induced preferential expansion of nodules formed with the most efficient partners when the symbiotic organs were functional. The response of nodule expansion was associated with the stimulation of symbiotic plant cell multiplication and of bacteroid differentiation. A general model where local and systemic N signaling mechanisms modulate interactions between Medicago truncatula and its Sinorhizobium partners is proposed.