We describe a patient with depression who was well controlled with sertraline monotherapy developing two relapses of depression in close temporal relationship with starting ayurvedic herbal mixtures. We discuss the possibility of a pharmacokinetic herb-drug interaction decreasing the therapeutic efficacy of sertraline leading to the relapses of depression. We speculate the herbal plant most likely to be responsible for this interaction is either Terminalia chebula or Commiphora wighteii.