This is an investigation into the finding that patients with primary hyperparathyroidism caused by Water Clear Cell Hyperplasia (WCCH) frequently belong to blood group O. Two control groups were defined from the same time period as 32 cases of WCCH treated at our clinic: one was a consecutive patient series with other forms of primary hyperparathyroidism (n = 864) and the other was the population in a geographically defined area in Sweden (n = 59,862). The blood group distribution of the patients with WCCH differed from the distribution of the patients with other forms of primary hyperparathyroidism with high significance (P = 0.00040). The blood group distribution did not differ between the two control groups. Strong associations between disease and HL-A type have previously been described, while associations found between disease and ABO blood groups were weaker. The association between WCCH and blood group O described here is by far the strongest association with the ABO system demonstrated to date. It is possible that the presence of an O-allele is a prerequisite for the development of WCCH.