To understand the natural history of retinal pigment epithelial (RPE) detachments (PEDs) associated with drusen, we retrospectively reviewed 125 PEDs that had not undergone laser treatment over an average follow-up period of 28 months. We identified six types of RPE detachments: pseudo-vitelliform, confluent drusen, serous, vascular, and hemorrhagic lesions as well as PEDs associated with a retinal vascular abnormality. We correlated the type of detachment with visual acuity and anatomic outcome. The poorest results were obtained for PEDs associated with neovascularization (vascular, hemorrhagic, and retinal vascular abnormality types). Eyes presenting with pseudo-vitelliform lesions or confluent drusen had the best visual prognosis and anatomic results. Obvious subretinal new vessels developed in 16 (34%) of the serous PEDs over an average follow-up period of 25 months. Subretinal neovascularization was rare in the pseudo-vitelliform and confluent drusen groups. The proposed classification system may be useful in predicting the natural course of PEDs.