Previously we showed that a single local injection of the avian paramyxovirus Newcastle disease virus (NDV) strain 73-T caused long-lasting, complete tumor regression of human neuroblastoma and fibrosarcoma xenografts in athymic mice. Here we report the antitumor effects of NDV administered by either the intratumoral (IT) route to treat a variety of human carcinoma xenografts or by the systemic (intraperitoneal, IP) route to treat neuroblastoma xenografts (6.5-12 mm in diameter). For IT treatments, mice were randomized into treatment groups and given a single IT injection of NDV 73-T, vehicle (phosphate buffered saline, PBS), or UV-inactivated NDV. For systemic therapy, mice (n=18) with subcutaneous IMR-32 human neuroblastoma xenografts received IP injections of NDV (5 x 10(9) PFU). Significant tumor growth inhibition (77-96%) was seen for epidermoid (KB8-5-11), colon (SW620 and HT29), large cell lung (NCIH460), breast (SKBR3), prostate (PC3), and low passage colon (MM17387) carcinoma xenografts treated IT with NDV. In all cases, tumors treated IT with PBS or replication-incompetent, UV-inactivated NDV displayed rapid tumor growth. After a single IP injection of NDV, complete regression of IMR-32 neuroblastomas was observed in 9 of 12 mice without recurrence for the 3-9 month follow-up period. Six mice with recurrent neuroblastomas after one IP injection received one to three additional IP treatments with NDV. Three of these six mice showed complete regression without recurrence. These data show that: (1) NDV administered either IT or IP is an effective antitumor therapy in this system, (2) replication competency is necessary for maximal effect, and (3) multiple NDV doses can be more effective than a single dose. These studies provide further rationale for the preclinical study of NDV as an oncolytic agent.