Objective: An association between allergic disease and depression has been consistently reported, but whether the key mediating ingredients are predominantly biological, psychological, or mere artifacts remains unknown. In the current study, we examined a hypothesized relationship between allergen-specific immunoglobulin E (IgE) status and changes in allergy symptoms with worsening in depression scores. Methods: In patients with recurrent mood disorders, we individually coupled sensitization to specific seasonal aeroallergens (as assessed by allergen-specific IgE) with temporal windows of exposure to aeroallergens (low versus high tree or ragweed pollen counts, measured according to the National Allergy Bureau guidelines). We compared Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) depression score changes in 41 patients with mood disorders [25 with major depression and 16 with bipolar I disorder, diagnosed by Structured Clinical Interview for DSM (SCID)] seropositive for tree or ragweed pollen-specific IgE antibody versus 53 patients with mood disorders (30 with major depression and 23 with bipolar I disorder) seronegative for aeroallergen-specific IgE. Results: Worsening in total depressive scores from low to high pollen exposure was greater in allergen-specific IgE-positive patients as compared to allergen-specific IgE antibody-negative patients (p = 0.01). When stratified by polarity, the association was significant only in patients with bipolar I disorder (p = 0.004). This relationship was resilient to adjustment for changes in allergy symptom scores. Conclusion: To our knowledge, this is the first report of coupling a molecular marker of vulnerability (allergen-specific IgE) with a specific environmental trigger (airborne allergens) leading to exacerbation of depression in patients with bipolar I disorder.