A common strategy to reveal the components of the speech production network is to use psycholinguistic manipulations previously tested in behavioral protocols. This often disregards how implementation aspects that are nonessential for interpreting behavior may affect the neural response. We compared the electrophysiological (EEG) signature of two popular picture naming protocols involving either unfamiliar pictures without repetitions or repeated familiar pictures. We observed significant semantic interference effects in behavior but not in the EEG, contrary to some previous findings. Remarkably, the two protocols elicited clearly distinct EEG responses. These were not due to naming latency differences nor did they reflect a homogeneous modulation of amplitude over the trial time-window. The effect of protocol is attributed to the familiarization induced by the first encounter with the materials. Picture naming processes can be substantially modulated by specific protocol requirements controlled by familiarity and, to a much lesser degree, the repetition of materials.