ABSTRACTThis review is intended to guide primary care providers in differentiating patients with bipolar depression from those with unipolar depression and inform patient management. Up to 64% of clinical encounters for depression occur in primary care, with misdiagnosis of bipolar depression common in both primary care and psychiatry. Although bipolar disorder is characterized by manic, hypomanic, and depressive episodes, the most common and debilitating symptomatic presentation is depression. Misdiagnosis as unipolar depression is common, often resulting in mistreatment with an unopposed monoamine antidepressant. Antidepressants are often ineffective for treating bipolar depression and may cause detrimental consequences such as treatment-emergent hypomania/mania, rapid cycling, or increased suicidality. Factors that are suggestive of bipolar disorder versus unipolar depression include early-onset depression, frequent depressive episodes, family history of serious mental illness, hypomania/mania symptoms within the depressive episode, and nonresponse to antidepressants. Comorbid medical (e.g., cardiovascular disease, hypertension, obesity) and psychiatric (e.g., attention-deficit/hyperactivity disorder, anxiety disorder, personality disorders, and substance use disorder) conditions are common and contribute to premature mortality for patients with bipolar disorder compared with the general public. Cariprazine, fluoxetine/olanzapine, lurasidone, and quetiapine are approved to treat bipolar depression; only cariprazine and quetiapine are approved to treat both bipolar mania and depression. Primary care providers who can differentiate presenting symptoms of bipolar depression from unipolar depression and offer appropriate treatment options will optimize patient care in clinical practice. Relevant information for this review was identified through a multistep literature search of PubMed using the terms bipolar depression/bipolar disorder plus other relevant terms.