The role of cognitive control mechanisms in reducing interference from emotionally salient distractors was investigated. In two experiments, participants performed a flanker task in which target-distractor affective compatibility and cognitive load were manipulated. Differently from past studies, targets and distractors were presented at separate spatial locations and cognitive load was not domain-specific. In Experiment 1, words (positive vs. negative) and faces (angry, happy or neutral faces), were used respectively as targets and distractors, whereas in Experiment 2, both targets (happy vs. angry) and distractors were faces. Findings showed interference from distractor processing only when cognitive load was high. The present findings indicate that, when targets and distractors are presented at different spatial locations, cognitive control mechanisms are involved in preventing interference from positive (Exp. 1) or negative distractors (Exp. 2). The role of stimulus valence and type is also discussed with regard to different patterns of interference observed.