This work presents the synthesis of nearly defect-free ZSM-5 nanosized crystals, prepared in fluoride medium by seeding with silicalite-1. This material was carefully characterized and its catalytic performances in the methanol to hydrocarbons (MTH) reaction were assessed. Such fluoride-based material was compared to a reference ZSM-5, produced through a conventional alkaline synthesis but from the same seeding. Despite both the materials show closely identical morphology and they have a comparable acid site population, the catalyst prepared using the fluoride route showed significantly longer lifetime in MTH compared to the catalyst prepared using conventional synthesis at high pH. The slower deactivation for the samples prepared using the fluoride route was ascribed, thanks to a thorough in situ IR spectroscopy study, to its lower density of internal defects. According to the UV-Raman characterization of coke on the spent catalyst, the fluoride-based ZSM-5 catalyst produces less molecular coke species, most probably because of the absence of enlarged cavities/channels as due to the presence of internal defects. On the basis of these observations, the deactivation mechanism in the ZSM-5 synthesized by fluoride medium could be mostly related to the deposition of an external layer of bulk coke, whereas in the alkali-synthesized catalyst an additional effect from molecular coke accumulating within the porous network accelerates the deactivation process.