Our objective was to determine whether the use of unilateral atropine as amblyopia therapy leads to an asymmetric change in refractive error compared with patching. Patients were enrolled in a clinical trial in which atropine 1% solution or occlusion with an adhesive patch was administered daily to the sound eye of children 3 to less than 7 years of age for a period of at least 6 months to a maximum of 2 years. Refractive error at entry and at 2 years was determined with cycloplegic retinoscopy for 282 of 419 patients enrolled. The baseline mean refractive error was + 3.13 diopters (D) in patients assigned randomly to receive atropine and + 2.58 D in patients assigned randomly to wear the patch. The mean change in refractive error of the sound eye was + 0.10 D in the atropine group (N = 134) and + 0.08 D in the patch group (N = 148). Patients also were subdivided into those treated with atropine only (n = 41) and patching only (n = 64) because some children changed treatments during their study participation. The mean change for the sound eyes was -0.21 D for the patients receiving only atropine and -0.06 D for the patients receiving only patching. Unilateral atropine applied to the sound eye compared with occlusion was not associated with any adverse effect on refractive error following up to 2 years of treatment.