The aim of this study was to make an inventory of the clinical signs of high-pathogenicity avian influenza (HPAI), to facilitate the development of an operational syndrome-reporting system (SRS) in The Netherlands as an early warning system for HPAI outbreaks. A total of 537 poultry flocks (240 infected and 297 non-infected) with a clinical suspicion of an infection with HPAI virus were investigated with respect to the clinical signs observed. Standardized reports were analysed with respect to observed clinical signs in the flocks. Various poultry types were distinguished. In infected commercial flocks with egg-producing chickens, the presence of increased mortality, apathy, coughing, reduction in normal vocalization, or pale eggs appeared to be overall the most sensitive indicators to detect a HPAI outbreak, matching a sensitivity of 99% with a specificity of 23%. In infected turkey flocks, the presence of apathy, decreased growth performance, reduction of normal vocalization, swollen sinuses, yawning, huddling, mucosal production from the beak, or lying down with an extended neck appeared to be overall the most sensitive indicators to detect a HPAI outbreak, matching a sensitivity of 100% with a specificity of 79%. In infected backyard/hobby flocks, increased mortality or swollen head appeared to be overall the most sensitive indicators of a HPAI outbreak, matching a sensitivity of 100% with a specificity of 26%. These results indicate that there is a solid basis for the choice of using increased mortality in the operational SRS in The Netherlands as an early warning system for HPAI outbreaks. The presence of apathy, specifically for turkeys, should be added to the SRS as an indicator.