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HIV-C (HIV-C) accounts for >56% of all HIV infections worldwide. To investigate vaccine safety and efficacy in non-human primates, a pathogenic, R5-tropic, neutralization sensitive simian-human immunodeficiency virus (SHIV) encoding HIV-C env would be desirable. We have constructed SHIV-2873Ni, an R5 SHIV encoding a primary pediatric HIV-C env isolated from a 2-month old Zambian infant, who progressed to death within one year of birth. SHIV-2873Ni was constructed using SHIV-1157ipd3N4 (Song et al., J. Viol. 80:8729-38, 2006) as backbone since the latter contains additional NF-κB sites in the long terminal repeats (LTRs) to enhance viral replicative capacity. The parental virus, SHIV-2873Ni, was serially passaged through 5 rhesus monkeys (RM); SHIV-2873Nip, the resulting passaged virus, was reisolated from the 4th recipient about 1 year post inoculation. SHIV-2873Nip was replication-competent in RM peripheral blood mononuclear cells (PBMC) of all random donors tested, was exclusively R5 tropic and its env gene clustered with HIV-C by phylogenetic analysis; its high sensitivity to neutralization led to a classification as Tier 1 virus. Indian-origin RM were inoculated by different mucosal routes, resulting in high peak viral RNA loads. Signs of virus-induced disease include depletion of gut CD4+ T lymphocytes, loss of memory T cells in blood, and thrombocytopenia that resulted in fatal cerebral hemorrhage. SHIV-2873Nip is a highly replication-competent, mucosally transmissible, pathogenic R5 virus that will be useful to study viral pathogenesis and to assess the efficacy of immunogens targeting HIV-C Env.