Affect can directly influence memory storage and retrieval, which offers the opportunity to improve memory performance by changing affective responses. A promising target is the left dorsolateral prefrontal cortex (dlPFC), as it is functionally involved in both affect and memory. This study explores whether anodal transcranial direct current stimulation (tDCS) to the left dlPFC improves memory retrieval through the reduction of negative affect and if this interacts with age. We randomly assigned 94 healthy individuals (n = 43 young, n = 51 elderly) to either sham or active tDCS during encoding of a verbal episodic memory task. Participants completed two questionnaires assessing affective states pre-and post-stimulation. They had to recall items unexpectedly 20 min after encoding and to name which feelings were associated with this free recall. We applied mediation models to explore the relation between tDCS, change in affect, and memory retrieval. In young participants, the reduction of negative affect via anodal tDCS fully mediated the increase in memory retrieval (R 2 = 57%; p < 0.001); that is, a stronger reduction of negative affect via tDCS led to better memory performance. We did not observe these effects in the elderly. Our study provides a further link between affect and memory: as increased activity in the dlPFC is crucial for successfully coping with affective interference, anodal tDCS seems to help preventing irrelevant negative thoughts, thus foster attention allocation. Studies applying anodal tDCS to the left dlPFC in healthy young participants should consider changes in affect when interpreting the effect of stimulation on memory performance.

The role hemispheric lateralization in the prefrontal cortex plays for episodic memory formation in general, and for emotionally valenced information in particular, is debated. In a randomized, double-blind, and sham-controlled design, healthy young participants (n = 254) performed 2 runs of encoding to categorize the perceptual, semantic, or emotionally valenced (positive or negative) features of words followed by a free recall and a recognition task. To resolve competing hypotheses about the contribution of each hemisphere, we modulated left or right dorsolateral prefrontal cortex (DLPFC) activity using transcranial direct current stimulation during encoding (1 mA, 20 min). With stimulation of the left DLPFC, but not the right DLPFC, encoding and free recall performance improved particularly for words that were processed semantically. In addition, enhancing left DLPFC activity increased memory formation for positive content while reducing that for negative content. In contrast, promoting right DLPFC activity increased memory formation for negative content. The left DLPFC assesses semantic properties of new memory content at encoding and thus influences how successful new episodic memories are established. Hemispheric laterlization—more active left DLPFC and less active right DLPFC—at the encoding stage shifts the formation of memory traces in favor of positively valenced content.