Thrombocytopenia can occur from a variety of etiologies. Drug-induced thrombocytopenia is known to occur with beta-lactam medications, but often in the setting of prolonged use. We describe 2 patients who developed rapid-onset thrombocytopenia from piperacillin/tazobactam. Other causes of immediate thrombocytopenia were excluded. These cases describe a rare presentation of rapid-onset thrombocytopenia in a commonly used medication.