Outbreaks of Highly Pathogenic Avian Influenza (HPAI) subtype H5N1 occurred previously for three consecutive years, 2006, 2007 and 2008 in Kano State, Nigeria, causing heavy economic losses to farmers and the government. It was against this background that risk factors for the occurrence and spread of HPAI H5N1 among commercial poultry farms in the State were evaluated. A total of 64 farms comprising 32 affected (AF) and 32 non-affected (NAF) farms were enrolled for this study. Questionnaires were designed and administered to the selected farms through interviews with farm owners or farm managers during on-site visits. Information on flock profile including farm characteristics and environment, husbandry practices, biosecurity practices, farm trade practices and employee activities were obtained and analyzed. Pearson Chi square and Fisher’s exact tests were used to compare categorical variables. Values of p< 0.05 were considered significant. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to measure the strength and statistical significance of associations between the variables and occurrence and spread of HPAI H5N1 in commercial poultry farms in the State. The most significant risk factors were the presence of untreated surface water on farms (OR 18.6, 95%CI 2.24 – 154.34, p = 0.001), exchange of egg crates between traders and farmers (OR 12.1, 95%CI 1.43 – 102.61, p = 0.006), allowing egg crates of traders into poultry pens (OR 11.67, 95%CI 2.37 – 57.86, p = 0.001) and allowing rodents/wild birds access to poultry feed (OR 3.65, 95%CI 0.23 – 1.87, p = 0.024). It was recommended that veterinary inspection to enforce and encourage best biosecurity practices for the poultry farms should be introduced and sustained.