The yellow clam Amarilladesma mactroides (Deshayes, 1854) is considered a vulnerable species since the mid-1990s. Populations have experienced mass mortalities throughout their entire range of distribution (23–41°S) along exposed sandy beaches of Atlantic South America. Detrimental anthropogenic impacts have further contributed to failure of populations to make a recovery. To determine the factors involved in these events, density prior to a mortality event was calculated and live yellow clams encompassingmost of its geographic range distribution were analyzed histologically to describe parasites and pathologies. Moreover, moribund specimens were analyzed by molecular techniques to test for the presence of the virus OsHV-1. A mortality event was recorded after a maximum density of 127 clams/m2 was attained. No clear pattern was found between the prevalence and intensity of infection and localities, mortality events, or sampling season. Although OsHV-1 was not observed in any of the yellow clams tested, the possibility that another viral agent was implicated cannot be ruled out. The presence of bacteria of the genus Vibrio in combination with stress caused by a relatively high population density is suggested as the likely cause of these episodic mass mortalities.