The effect of proximity on infected premises was evaluated during the highly pathogenic avian influenza (HPAI) epidemic that struck northern Italy in 1999–2000 by quantifying the spatial and temporal clustering of cases. The epidemic was caused by an H7N1 subtype of type A influenza virus that originated from a low-pathogenic AI virus that spread among poultry farms in northeastern Italy in 1999 and eventually became virulent by mutation. More than 90% of 413 infected premises were located in Lombardy and Veneto regions; of 382 outbreaks, 60% occurred in the Lombardy region and 40% in the Veneto region. Global and local spatial statistics were used to estimate the location and degree of clustering of cases with respect to the population at risk. Outbreaks were spatially clustered primarily in Lombardy, with a large cluster in Brescia province and another in Mantua province, on the border of Veneto. Time series analysis was used to assess the temporal clustering of outbreaks. Temporal aggregation increased during the first 5 wk and decreased thereafter (probably as a result of eradication measures enforced in the Veneto region). Spatio-temporal clustering was assessed considering the Temporal Risk Window (TRW), the time period during which premises remain infectious and infection can spread to neighboring premises. The clustering pattern was similar to the one detected when considering spatial clustering (i.e., the larger clusters were identified in the Brescia and Mantua provinces of Lombardy). These results highlight the role of proximity in the spread of AI virus and, when considering the TRW, indicate the possible direction of virus spread.