Aim To compare the outcomes of autologous platelet rich plasma (PRP) eye drops and inferior silicone punctal plugs in the treatment of moderate to severe dry eye disease (DED). Patients and methods This retrospective non-randomized comparative study included 46 patients with bilateral moderate to severe DED during the period from May 2021 to June 2022. They were divided into two groups, Group I: patients treated with autologous PRP eyedrops and Group II: patients treated with an inferior silicone punctal plug. The mean values of ocular surface disease index (OSDI), Schirmer’s test (ST), fluorescein break up time (FBUT), and corneal fluorescein staining (CFS) were calculated for each group at baseline and at 2 weeks, 1 month, and 3 months followup. Mean posttreatment values were compared with baseline in each group. Mean values at baseline and at each follow up visit were compared between the two groups. Any complications were recorded. Results Group I included 50 eyes of 25 patients while group II included 42 eyes of 21 patients. Both groups showed statistically significant improvement in all DED parameters posttreatment compared with baseline (P<0.05). There was no statistically significant difference between the two groups regarding DED parameters at baseline and each follow-up visit (P>0.05). Reported complications were spontaneous loss of the plug in 19 (45.2%) eyes and persistent epiphora in 2 (4.8%) eyes in group II. No complications were noted in group I. The difference in complication rates between the two groups was highly significant (P<0.001). Conclusion Both autologous PRP eyedrops and inferior silicone punctal plugs are effective in the treatment of moderate to severe DED. However, inferior silicone punctal plugs are associated with more complications.