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PurposeTo provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment.MethodsASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel.ResultsSix new or updated meta-analyses and six new primary studies were added to the updated systematic review.RecommendationsAntibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus–seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. Additional information is available at www.asco.org/supportive-care-guidelines.