The “Cayuga syndrome” is a maternally transmitted, naturally occurring thiamine deficiency that causes 100% mortality of larval landlocked Atlantic salmon Salmo salar in several of New York's Finger Lakes, Results of multiyear studies to qualify and quantify the neurobehavioral and gross pathological signs of this condition are described, Affected sac fry became weak and ataxic and responded atypically to stimuli 1–2 weeks before death. Quantitative assays of stimulus-provoked swimming revealed a significant neuropathy whereby the sac fry exhibited abnormal thigmotactic and phototactic behaviors. Gross lesions observed in Cayuga sac fry included yolk-sac opacities, subcutaneous edema, vitelline hemorrhage or congestion, pericardial edema, retrobulbar edema, branchial congestion, foreshortened maxillae, hydrocephalus, and occasional caudal fin deformities, Lesion frequency in progeny differed significantly between dam source. Yolk conversion efficiency was decreased at least 1 week before death, suggesting that the bioenergetics of the fish was compromised and thereby supporting the thiamine residue and treatment data reported elsewhere, Comparisons with coagulated-yolk, blue-sac and swim-up syndromes are presented, The pathological signs of the Cayuga syndrome represent a unique departure from the lesions induced by toxicants or pathogens in other piscine models, and for the first time profile the profound effects of thiamine deficiency on cardiovascular and neurological systems of larval fish.