The presence of a P1-active substance in hydatid cyst fluid has been known since 1957. Recent work has revealed the presence of high-titer anti-P1 antibodies in blood group P2 patients with Fasciola hepatica infection (distomiasis). These findings, together with the observation of a high percentage of cross-reactions in the hydatid indirect hemagglutination test (IHA) among distomiasis patients, led us to study the possible role played by anti-P1 antibodies in the occurrence of these nonspecific reactions. Of the 51 sera from patients with distomiasis studied, seven were IHA-positive. Of these, six presented high titer anti-P1 antibodies. Absorption of these sera with P1 erythrocytes eliminated their anti-P1 activity; at the same time, four of the sera became negative in the IHA test and the IHA titers of the two remaining sera decreased without disappearing entirely. Results with two reference animal anti-P1 sera confirmed these findings. The agar gel diffusion reaction revealed cross-reactions in addition to the P1-anti-P1 precipitin line. The negative results obtained with seven high titer anti-P1 distomiasis sera and 21 control sera from patients without hydatidosis, which showed a weak “naturally-occurring” anti-P1 activity, led us to discuss the conditions necessary for the reaction between anti-P1 and P1 antigen of hydatid cyst fluid to be detectable by IHA at levels significant for serodiagnosis of hydatidosis. Finally, the importance of further work to improve the specificity of the quantitative methods for serodiagnosis of hydatid disease without impairing their sensitivity is emphasized.