Since 2003, highly pathogenic avian influenza (HPAI) H5N1 virus has spread, causing a pandemic with serious economic consequences and public health implications. Quantitative estimates of the spread of HPAI H5N1 are needed to adapt control measures. This study aimed to estimate the variations of the reproduction number R in space and time for the HPAI H5N1 epidemic in Thailand. Transmission between sub-districts was analyzed using three different and complementary methods. Transmission of HPAI H5N1 was intense (R(t) > 1) before October 2004, at which point the epidemic started to progressively fade out (R(t) < 1). The spread was mainly local, with 75% of the putative distances of transmission less than 32 km. The map of the mean standardized ratio of transmitting the infection (sr) showed sub-districts with a high risk of transmitting infection. Findings from this study can contribute to discussions regarding the efficacy of control measures and help target surveillance programs.