Perinatal depression affects 10-20% of women and is associated with poor outcomes for mother and child. Inflammation is associated with depression in non-pregnant adults. Perinatal depression and inflammation in pregnancy are independently associated with morbidities including obesity, gestational diabetes, preeclampsia, and preterm birth. The role of inflammation in perinatal depression has received little attention. We hypothesized an association between self-reported perinatal depressive symptoms and serum inflammatory biomarkers TNF-α, IL-6, IL-1β, and CRP. 110 healthy gravidas were recruited in third trimester from an academic medical center, with a baseline study visit at a mean of 32.5 (SD ± 1.8) weeks gestational age. Sixty-three participants completed the Edinburgh Postnatal Depression Scale (EPDS) and provided demographic information and serum samples upon enrollment and at 3 and 6 months postpartum. Serum inflammatory markers were quantified by multiplex array. Multiple linear mixed effects models were used to evaluate trends of biomarkers with the EPDS score in the third trimester of pregnancy and the postpartum period. Elevated serum TNF-α was associated with lower EPDS total score (β = - 0.90, p = 0.046) after adjusting for demographics and medication use. In contrast, IL-6, CRP, and IL-1β did not demonstrate statistically significant associations with depressive symptoms by the EPDS in either crude or adjusted models. Study findings showed no association or an inverse (TNF-α) association between inflammatory markers and perinatal depressive symptoms. Relevant literature evaluating a role for inflammation in depression in the unique context of pregnancy is both limited and inconsistent, and further exploration is merited.