Echinacea is an herbal supplement commonly used as an immune system stimulant to prevent infections, such as the common cold or flu. Echinacea has been documented as a cyctochrome P450 (CYP) 3A4 inhibitor in vitro, but no formal studies have been conducted in humans. Etoposide is a cytotoxic, topoisomerase II inhibitor, chemotherapeutic agent used in the treatment of lung cancer. Etoposide is primarily metabolized by CYP 3A4. We report the first possible drug-herbal interaction between Echinacea and etoposide. A 61-year-old gentleman newly diagnosed with nonsmall cell lung cancer began concurrent chemoradiation with cisplatin and etoposide. He was admitted to the hospital on day 8 of his first cycle and found to be thrombocytopenic. His platelet count eventually reached a nadir of 16 × 10(3)/L, requiring platelet transfusion support. Upon admission, it was discovered he was taking Echinacea, which was discontinued. He received his next cycle of chemotherapy without taking Echinacea. His platelet count decreased to a nadir of 44 × 10(3)/L, but he did not require platelet transfusions. Echinacea likely contributed to this patient's profound thrombocytopenia and should be avoided in patients receiving etoposide and possibly other chemotherapeutic drugs that are CYP 3A4 substrates.