A series of case reports and anecdotal references describe the adverse effects on human health ascribed to the marine toxin palytoxin (PLTX) after different exposure routes. They include poisonings after oral intake of contaminated seafood, but also inhalation and cutaneous/systemic exposures after direct contact with aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing cnidarian zoanthids. The symptoms commonly recorded during PLTX intoxication are general malaise and weakness, associated with myalgia, respiratory effects, impairment of the neuromuscular apparatus and abnormalities in cardiac function. Systemic symptoms are often recorded together with local damages whose intensity varies according to the route and length of exposure. Gastrointestinal malaise or respiratory distress is common for oral and inhalational exposure, respectively. In addition, irritant properties of PLTX probably account for the inflammatory reactions typical of cutaneous and inhalational contact. Unfortunately, the toxin identification and/or quantification are often incomplete or missing and cases of poisoning are indirectly ascribed to PLTXs, according only to symptoms, anamnesis and environmental/epidemiological investigations (i.e. zoanthid handling or ingestion of particular seafood). Based on the available literature, we suggest a “case definition of PLTX poisonings” according to the main exposure routes, and, we propose the main symptoms to be checked, as well as, hemato-clinical analysis to be carried out. We also suggest the performance of specific analyses both on biological specimens of patients, as well as, on the contaminated materials responsible for the poisoning. A standardized protocol for data collection could provide a more rapid and reliable diagnosis of palytoxin-poisoning, but also the collection of necessary data for the risk assessment for this family of toxins.