To study the natural course of staphyloma-induced serous maculopathy (SISM) and the effects of treatments. Retrospective case series. This retrospective analysis included 26 eyes of 20 patients with SISM and at least 12 months of follow-up. Medical records were reviewed for patient demographics, such as age, sex, spherical equivalent, best-corrected visual acuity (BCVA), type of staphyloma, and imaging characteristics. Spectralis OCT B-scans were evaluated for the presence and height of the serous retinal detachment (SRD) at each follow-up visit. An SRD episode was defined as a period with SRD in 1 patient. Changes in SRD height and BCVA. Twenty-six eyes of 20 patients (70% female) were included. The mean age was 54 ± 11 years, and the mean spherical equivalent was -4.8 ± 3.3 diopters at baseline. The staphyloma was located inferior in 12 eyes (46%), inferonasal in 7 eyes (27%), and nasal in 7 eyes (27%). The mean follow-up duration was 73 ± 34 months. During follow-up, the SRD height fluctuated in all eyes, with a mean change of 125 ± 56 μm. The SRD disappeared completely during follow-up in 13 eyes (50%) and then reappeared in 7 eyes (35%). Resolution occurred spontaneous in 8 eyes (31%). The median time of an SRD episode was 25 (interquartile range 14-57) months. Treatment was performed in 20 eyes (77%) and led to resolution of SRD in 3 of the 15 photodynamic therapy treatments (21%), 2 of 5 (40%) anti-VEGF series, and 2 of 4 eyes (50%) treated with topical prednisolone. Best-corrected visual acuity at the final visit (0.42 ± 0.25) was not significantly different from BCVA at baseline (0.34 ± 0.27 logarithm of the minimum angle of resolution, P= 0.07), nor was BCVA change significantly different between treated eyes (n= 19) and nontreated eyes (n= 7, P= 0.3). Serous retinal detachment in patients with SISM fluctuated over time and resolved without treatment in 31% of the eyes. Because treatment does not change the course of BCVA, a wait-and-see policy is advocated in these patients on the exclusion of treatable causes of SRD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.