To test the hypothesis that activation asymmetries of the most anterior parts of the prefrontal cortex may be related to state-dependent regulation of emotion, spontaneous changes of cortical activation asymmetries from one session to a second one were related to spontaneous mood changes in two large samples (ns = 56 and 128). The interval between sessions was 2 to 4 weeks. Results show that mood changes specifically covary with changes of EEG asymmetry at the frontopolar electrode positions, but not with changes at other locations (dorsolateral frontal, temporal, and parietal). Anxiety, tension, and depression were found to decrease when frontopolar activation asymmetry shifted to the right. Taking the new findings into account may contribute to the refinement and extension of theories on EEG laterality and emotion.