Temporolimbic circuits play a crucial role in the regulation of human emotion. A highly sensitive single-shot multiecho functional magnetic resonance imaging (fMRI) technique with gradient compensation of local magnetic field inhomogeneities and real-time data analysis were used to measure increases in amygdala activation during single 60-s trials of self-induced sadness. Six healthy male and female subjects performed a validated mood induction paradigm with randomized presentation of sad or neutral faces in 10 trials per scan. Subjects reported the intensity of experienced sadness after each trial. Immediate feedback of amygdala activation was given to the subjects during the ongoing scan to reinforce mood induction. Correspondence between increased intensity of predominantly left sided amygdala activation and self-rating of sadness was found in 78% of 120 sad trials, in contrast to only 14% of neutral trials. Amygdala activation was reproducible during repeated scanning sessions and displayed the strongest correlation with self-rating among all regions. These results suggest that amygdala activation may be closely associated with self-induced sadness. This novel real-time fMRI technology is applicable to a wide range of neuroscience studies, particularly those of the limbic system, and to neuropsychiatric conditions, such as depression, in which pathology of the amygdala has been implicated.