The neural circuits that regulate placebo analgesia responsivity are unknown, although engagement of brainstem pain modulatory regions is likely critical. Here we show in 47 participants that differences are present in neural circuit connectivity’s in placebo responders versus non-responders. We distinguish stimulus-independent and stimulus-dependent neural networks that display altered connections between the hypothalamus, anterior cingulate cortex and midbrain periaqueductal gray matter. This dual regulatory system underpins an individual’s ability to mount placebo analgesia.