This study investigated whether in a stimulus–response compatibility (SRC) task affordance effects in response to picture of graspable objects emerge when these objects appear as already grasped. It also assessed whether the observed effects could be explained as due to spatial compatibility between the most salient part in the object/display and the hand of response rather than to action potentiation. To this aim, we conducted three behavioural experiments in which participants were required to discriminate the vertical orientation (upright vs. inverted) of an object presented in the centre of the screen, while ignoring the right–left orientation of its handle. The object could be presented alone, as already grasped, as partially masked (Experiment 1) or with a human hand close to its graspable side (Experiment 2). In addition, to assess the role of perceptual salience, the object could be presented with a human hand or a non-biological (a geometrical shape) distractor located opposite to the object’s graspable side. Results showed faster responses when the object’s handle was located on the same side of the responding hand with a larger effect when upright objects were shown as already grasped (Experiment 1) or when a hand was displayed close to its handle (Experiment 2), and a smaller reversed effect when the hand or the geometrical shape was located opposite to the handled side (Experiment 3). We interpreted these findings as indicating that handle orientation effects emerging in SRC tasks may result from the interplay between motor affordance and spatial compatibility mechanisms.