A case-control study was conducted among commercial table-egg layer and pullet operations in Iowa and Nebraska, United States, to investigate potential risk factors for infection with highly pathogenic avian influenza (HPAI) H5N2. A questionnaire was developed and administered to 28 case farms and 31 control farms. Data were collected at the farm and barn levels, enabling two separate analyses to be performed—the first a farm-level comparison of case farms vs. control farms, and the second a barn-level comparison between case barns on case farms and control barns on control farms. Multivariable logistic regression models were fit using a forward-selection procedure. Key risk factors identified were farm location in an existing control zone, rendering and garbage trucks coming near barns, dead-bird disposal located near barns, and visits by a company service person. Variables associated with a decreased risk of infection included visitors changing clothing, cleaning and disinfecting a hard-surface barn entryway, and ceiling/eaves ventilation in barns.