Forty-nine 5-week-old chickens were inoculated by the intravenous (i.v.), intratracheal (IT), or intranasal (IN) routes with either a chicken-origin or one of two duck-origin type A influenza virus isolates. Twelve control chickens were inoculated with sterile chorioallantoic fluid. For all viruses, i.v. inoculation produced predominate lesions of renal tubule necrosis (nephrosis) and nephritis, and influenza virus nucleoprotein was localized in nuclei and cytoplasm of necrotic renal tubule epithelium. Chickens inoculated by the IT route, and to a lesser extent the IN route, had mild to severe tracheitis, bronchitis, and ventromedial pneumonia associated with secondary bronchi but lacked renal tubule necrosis and nephritis. These data indicate low-virulence avian-origin influenza viruses were nephrotropic during simulated systemic infection (i.v. inoculation) and pneumotropic during simulated local infection (IT and IN inoculation). Gross and histologic kidney lesions produced by i.v. inoculation of the chicken-origin influenza virus were similar to changes reported in outbreaks of low-virulence influenza virus in laying chickens.