High erythropoietin (EPO) levels in cyst fluid and blood plasma in patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported. In the present study we assessed EPO levels and the biochemical composition of cyst fluid obtained from 50 simple renal cysts. Basing on cyst fluid/plasma sodium ratio 38 cysts were classified as cysts of proximal origin, and 12 as cysts of undetermined origin. EPO concentrations in cyst fluid obtained from proximal cysts were significantly higher than in fluid from cysts of undetermined origin (472.9 ± 116.2 vs. 122.1 ± 33.3 mU/ml, p < 0.05). Patients with proximal cysts had significantly higher plasma EPO levels (31.8 ± 3.5 mU/ml) than healthy subjects (17.3 ± 1.96 mU/ml, p < 0.005). We conclude that: (1) simple renal cysts of distal origin seem to be rare; (2) the presence of high EPO level in cyst fluid suggests its proximal origin; (3) estimation of cyst fluid EPO levels seems to be of similar pathogenetic value as the assessment of the cyst fluid/plasma sodium ra