The United States Centers for Disease Control and Prevention reported over 1000 cases of severe respiratory disease in pediatric patients associated with enterovirus D68 (EV-D68) in the fall of 2014. We sought to identify and define the clinical burden of disease due to EV-D68 in adult patients with hematologic malignancy or undergoing hematopoietic cell transplant (HCT). Real-time reverse-transcriptase polymerase chain reaction (PCR) for EV-D68 was performed on all respiratory samples positive for human rhinovirus (HRV) or negative for all respiratory viruses by a laboratory-developed respiratory viral PCR panel from August 11, 2014, to November 7, 2014. Presumptive cases were defined as those with an EV-D68 PCR cycle threshold (CT) at least 4 cycles lower than the HRV CT for HRV-positive samples or any EV-D68 CT value for HRV-negative samples. Sequencing of a 150-bp fragment of the 5\' noncoding region confirmed EV-D68 in 16 of 506 respiratory samples. Eight patients had a history of hematologic malignancy, and 6 of these had undergone HCT. Presentation ranged from mild upper respiratory symptoms to respiratory failure. EV-D68 can infect adult patients with hematologic malignancy and HCT recipients and may be associated with severe respiratory disease. Current commercial diagnostic assays cannot differentiate EV-D68 from other enteroviruses or HRV, and improved rapid diagnostic tools are needed.