OBJECTIVES: Sufficient prefrontal top-down control of limbic affective areas, especially the amygdala, is essential for successful effortful emotion regulation (ER). Difficulties in effortful ER have been seen in patients with bipolar disorder (BD), which could be suggestive of a disturbed prefrontal-amygdala regulation circuit. The aim of this study was to investigate whether BD patients show abnormal effective connectivity from the prefrontal areas to the amygdala during effortful ER (reappraisal). METHODS: Forty participants (23 BD patients and 17 healthy controls [HC]) performed an ER task during functional magnetic resonance imaging. Using dynamic causal modeling, we investigated effective connectivity from the dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) to the amygdala, as well as connectivity between the DLPFC and VLPFC during reappraisal. RESULTS: Both BD patients and HC showed decreased negative affect ratings following reappraisal compared to attending negative pictures (P <.001). There were no group differences (P =.10). There was a differential modulatory effect of reappraisal on the connectivity from the DLPFC to amygdala between BD patients and HC (P =.04), with BD patients showing a weaker modulatory effect on this connectivity compared to HC. There were no other group differences. CONCLUSION: The disturbance in BD patients in effective connectivity from the DLPFC to the amygdala while reappraising is indicative of insufficient prefrontal control. This impairment should be studied further in relation to cycling frequency and polarity of switches in BD patients.