Purpose <p>To evaluate the additive effect of topical cyclosporine A (Cs-A) 0.05% eye drops with topical prednisolone compared with that of topical prednisolone acetate 1% eye drops alone for the treatment of herpetic stromal keratitis (HSK).</p> Methods <p>Patients diagnosed with HSK were randomly divided into 2 groups: Group A received Cs-A eye drops b.i.d. with prednisolone eye drops q.i.d.; Group B received topical prednisolone q.i.d. with placebo eye drops b.i.d.; both Groups A &amp; B received a systemic acyclovir therapeutic dose of 400&#xa0;mg five times daily, tapered to twice daily on the 10th day. Follow-up was performed weekly for 2 months. The primary outcome measures included duration of treatment, corneal edema (CE), haziness (CH), punctate epitheliopathy (CP) and vascularization (CV). The secondary outcome measures included best corrected visual acuity (BCVA) and intraocular pressure (IOP).</p> Results <p>Thirty eyes from 30 patients were included (15 in each group). At baseline, only the CP score was significantly greater in Group B. The duration of treatment was significantly shorter in Group A. At the 2-month follow-up, there were significant improvements in the CE, CH and CP scores in both groups compared with the baseline scores, but there were no significant differences between the groups. There was a significant improvement in BCVA in both groups compared with baseline scores, but there was no significant difference between the groups. Two patients in group B required topical drops to control the IOP.</p> Conclusion <p>The addition of Cs-A eye drops to the treatment protocol for HSK patients has a significant role in shortening the duration of treatment in the management of HSK patients with and without epithelial ulceration.</p> Registration <p>The study protocol was approved by the Local Review Board <b>(Registration code: 2261)</b>, and ClinicalTrials.gov <b>(ID: NCT05720715)</b>.</p>