Fundus autofluorescence is already used to evaluate inflammatory disorders affecting the chorioretinal interface. We investigated the autofluorescence characteristics of two cases of serpiginous choroiditis (SC) during recurrent acute episodes, and followed them until their resolution. We compared the autofluorescence findings with those obtained with other imaging techniques. Autofluorescence photographs of the eyes were taken in a 26-year-old female and a 68-year-old male with SC at the first appearance of active lesions and during a strict follow-up period. Patients had complete ophthalmological evaluations including optical coherence tomography (OCT) and fluorescein and indocyanine green (ICG) angiography. Autofluorescence findings were compared with features from other imaging techniques. Patients were treated with systemic or intravitreal steroids. Hyperautofluorescence was detected 2 to 5 days after the appearance of the lesions, providing a clear delineation of the area of definitive retinal pigment epithelium (RPE) damage. This area was less extensive than the perfusion defect of the choriocapillaris indicated by ICG angiography. OCT showed very early increased reflectance of the photoreceptor layer in the area of hyperautofluorescence. A progressive decrease in autofluorescence was seen during the scarring phase of the disease. OCT changes in the photoreceptor layer were still present in the atrophic hypoautofluorescent lesions. Fundus autofluorescence seems to be a very sensitive imaging technique for detecting damage of the RPE in acute episodes of SC. A sequence of autofluorescence changes reflects the passage from activation to resolution of new lesions. Similarities, but also differences can be found by comparing our SC findings with those obtained with autofluorescence and OCT in posterior multifocal placoid pigment epitheliopathy.