Studies in experimental models of retinal detachment have proposed that the degree of visual recovery following retinal reattachment depends upon the extent of photoreceptor degeneration. A means of assessing this degeneration would help in establishing postoperative prognosis. S-antigen (S-Ag) is a unique retinal protein found in outer segment disc membranes and photoreceptor cells. In 36 cases of human rhegmatogenous retinal detachment, subretinal fluid (SRF) concentrations of S-Ag, measured by radioimmunoassay, ranged from 43 to 170 ng/ml (serum: 1-28 ng/ml). Analysis of variance showed a positive correlation with the duration of detachment (P less than 0.001). There was a two-fold increase in S-Ag concentrations during the first 2 weeks of detachment (P less than 0.005), with constant levels thereafter. These findings reflect progressive photoreceptor degeneration and/or ongoing synthesis of outer segment proteins in the detached retina that stop after the second week of detachment. SRF S-Ag levels may provide a prognostic indicator of visual recovery after reattachment as well as a sensitive measure of retinal metabolic activity during detachment.