Background: The purpose of this study is to evaluate the utility and safety of plasma rich in growth factors immunosafe eye drops (is-ePRGF) in the postoperative treatment of non-penetrating deep sclerectomy (NPDS). Methods: This is a case–control study in patients with open-angle glaucoma. Group one (control) was not treated with is-ePRGF, while group two (is-ePRGF) was treated (four times a day for four months). Postoperative evaluations were performed at one day, one month, three months and six months. The main outcomes were: intraocular pressure (IOP), microcysts in blebs with AS-OCT and the number of hypotensive eye drops. Results: Preoperatively, group one (n= 48 eyes) and group two (n= 47 eyes) were similar in age (71.5 ± 10.7 vs. 70.9 ± 10.0 years;p= 0.68), IOP (20.6 ± 10.2 vs. 23.0 ± 9.0 mmHg;p= 0.26) and number of hypotensive drugs (2.7 ± 0.8 vs. 2.8 ± 0.9;p= 0.40). The IOP at six months dropped to 15.0 ± 8.0 mmHg (IOP reduction: −27.2%) and 10.9 ± 4.3 mmHg (IOP reduction: −52.6%) for group one and group two, respectively (p< 0.01). At six months, blebs with microcysts were 62.5% (group one) and 76.7% (group two). Postoperative complications were observed in 12 eyes (25%) for group one and in 5 eyes (11%) for group two (p= 0.06). No specific complications related to the use of is-ePRGF were identified. Conclusions: Topical is-ePRGF seems to reduce IOP and the rate of complications in the medium term after NPDS, so it can be considered as a possible safe adjuvant to achieve surgical success.