Five outbreaks of H5N1 highly pathogenic avian influenza (HPAI) have been diagnosed in domestic poultry and wild birds in Cambodia from January to November of 2011. Of the five outbreaks, one occurred in a village backyard flock in Kandal province in January; two occurred in native Cambodian chickens and ducks in Banteay Meanchey province in July and August, respectively; one was seen in wild birds in Phnom Tamao Zoo in Kandal Province in July; and one outbreak occurred in commercial broilers at Opong Moan in Battambang province in northwestern Cambodia in early November. Clinically, HPAI-infected broilers and native chickens showed sudden death, severe depression, ruffled feathers, edema of heads and necks, swollen and cyanotic combs and wattles, and swollen and congested conjunctiva, with occasional hemorrhage, paralysis, and other neurologic signs. In ducks, significantly swollen sinuses and eyes, cloudy corneas, difficulty standing, or paralysis were commonly seen. Some affected ducks showed sudden death without obvious clinical symptoms. Necropsy lesions showed congestion and necrotic debris within sinuses and severe hemorrhages in gizzards, livers, and lungs in both affected native chickens and ducks during the new outbreaks in 2011. All five outbreaks were diagnosed as H5N1 HPAI by virus isolation and real-time reverse transcription–PCR tests. Once a backyard flock in a village or a poultry farm was diagnosed as positive for H5N1 HPAI; the whole village backyard poultry and all farm flocks were culled immediately by Cambodian provincial and central authorities as per the strategies adopted for the control of HPAI.