Objective: To describe the clinical characteristics, natural course, and complications of a large group of patients with primary iris pigment epithelium (IPE) cysts. Design: Observational case series. Participants: Two hundred thirty-four patients with primary IPE cysts participated. Results: Primary IPE cysts were classified as central in 6 patients (3%), midzonal in 50 patients (21%), peripheral in 170 patients (73%), and dislodged in 8 patients (3%). Central (pupillary) IPE cysts were found only in males, peripheral IPE cysts were found most often in females (69%), and no gender predilection was detected for midzonal and dislodged IPE cysts. Central and peripheral IPE cysts occurred in young patients (mean age, 20 and 33 years, respectively), whereas midzonal and dislodged IPE cysts were seen in slightly older patients (mean age, 52 and 45 years, respectively). Central IPE cysts were visible when the pupil was not dilated and appeared most often as a round or collapsed brown lesion arising from the pupillary margin, most commonly superonasally. Midzonal IPE cysts were brown and fusiform, best visualized after pupillary dilation. Peripheral IPE cysts produced a characteristic bulging in the iris stroma near the iris root, but they were directly visible in only 78% of cases. After wide dilation and patient and slit-lamp positioning, they appeared as a round clear lesion behind the iris, most often in the inferotemporal quadrant. Finally, dislodged IPE cysts appeared as a brown oval lesion, free floating in the anterior chamber (12%) or in the vitreous (12%), or fixed in the anterior chamber angle (75%). One hundred twenty-four patients (53%) were followed for a mean of 35 months (range, 3 months-19 years). In these patients, complications associated with IPE cysts included lens subluxation in one case (1%), iritis in one case (1%), focal cataract in two cases (2%), glaucoma in two cases (2%), and corneal touch in five cases (4%). Conclusion: Primary IPE cysts have characteristic clinical features that serve to differentiate them from intraocular malignancies. Most cysts have a benign clinical course, and treatment is rarely necessary.