Graphene has drawn a lot of interest in the material community due to unique physicochemical properties. Owing to a high surface area to volume ratio and free oxygen groups, the oxidised derivative, graphene oxide (GO) has promising potential as a drug delivery system. Here, we investigated in mice the lung tolerability of two distinct GO varying in lateral dimensions, to reveal the most suitable candidate platform for pulmonary drug delivery. Following repeated chronic pulmonary exposure to GO sheet suspensions, the innate and adaptive immune responses were studied. An acute and transient influx of neutrophils and eosinophils in the alveolar space, together with the replacement of alveolar macrophages by interstitial ones and a significant activation towards anti-inflammatory subsets, were found for both GO materials. Micrometric GO gave rise to persistent multinucleated macrophages and granulomas. However, neither adaptive immune response nor lung tissue remodelling were induced after exposure to micrometric GO. Concurrently, milder effects and faster tissue recovery, both associated to a faster clearance from the respiratory tract, were found for nanometric GO, suggesting a greater lung tolerability. Taken together, these results highlight the importance of dimensions in the design of biocompatible 2D materials for pulmonary drug delivery system.