This study quantifies the spatio-temporal association between outbreaks of highly pathogenic avian influenza H5N1 in domestic poultry (n = 3050) and human cases (n = 99) in Vietnam during 2003-2007, using rare events logistic regression. After adjusting for the effect of known confounders, the odds of a human case being reported to authorities increased by a factor of 6.17 [95% confidence interval (CI) 3.33-11.38] and 2.48 (95% CI 1.20 - 5.13) if poultry outbreaks were reported in the same district 1 week and 4 weeks later respectively. When jointly considering poultry outbreaks in the same and neighbouring districts, occurrence of poultry outbreaks in the same week, 1-week later, and 4 weeks later increased the odds of a human case by a factor of 2.75 (95% CI 1.43-5.30), 2.56 (95% CI 1.31-5.00) and 2.70 (95% CI 1.56-4.66) respectively. Our study found evidence of different levels of association between human cases and poultry outbreaks in the North and the South of the country. When considering the 9-week interval extending from 4 weeks before to 4 weeks after the week of reporting a human case, in the South poultry outbreaks were recorded in 58% of cases in the same district and 83% of cases in either the same or neighbouring districts, whereas in the North the equivalent results were only 23% and 42%. The strength of the association between human and poultry cases declined over the study period. We conclude that owner reporting of clinical disease in poultry needs to be enhanced by targeted agent-specific surveillance integrated with preventive and other measures, if human exposure is to be minimized.