Background. We conducted investigations in 2 villages in Cambodia where outbreaks of influenza H5N1 occurred among humans and poultry to determine the frequency of and risk factors for H5N1 virus transmission. Methods. During May 2006, ∼7 weeks after outbreaks of influenza H5N1 among poultry occurred, villagers living near households of 2 patients with influenza H5N1 were interviewed about potential H5N1 exposures and had blood samples obtained for H5N1 serological testing by microneutralization assay. A seropositive result was defined as an influenza H5N1 neutralizing antibody titer of ≥1:80, with confirmation by Western blot assay. A case-control study was conducted to identify risk, factors for influenza H5N1 virus infection. Control, subjects, who had seronegative results of tests, were matched with H5N1 -seropositive persons by village residence, households with an influenza H5Nl-infected poultry flock, sex, and age. Results. Seven (1.0%) of 674 villagers tested seropositive for influenza H5Nl antibodies and did not report severe illness; 6 (85.7%) were male. The 7 H5N1-seropositive persons, all of whom were aged ≤ 18 years, were younger than participants who tested seronegative for H5N1 antibodies (median age, 12.0 years vs. 27.4 years; P = .03) and were more likely than were the 24 control subjects to report bathing or swimming in household ponds (71.4% vs. 20.8%; matched odds ratio, 11.3; P = .03). Conclusions. Avian-to-human transmission of influenza H5N1 virus remains low, despite extensive poultry contact. Exposure to a potentially contaminated environment was a risk factor for human infection. © 2009 by the Infectious Diseases Society of America. All rights reserved.