To evaluate the efficacy and safety of autologous serum (AS) eye drops combined with punctal plugs (PPs) in patients with Sjögren syndrome (SS)-related dry eye. A retrospective clinical study was performed in patients with dry eye caused by SS. We evaluated the Schirmer test value, tear breakup time (tBUT), and fluorescein and Rose Bengal (RB) staining scores at baseline, 3 months, 6 months, 1 year, and >1 year after treatment. The dry eye indexes were also evaluated in 2 subgroups, which determined by the using of PPs, including the AS + PP group and AS only group. A total of 56 eyes of 28 patients were investigated with a mean follow-up of 42.3 ± 26.1 months. After the application of AS eye drops, the Schirmer test showed no significant changes. The tBUT (2.7 ± 1.9 seconds) was significantly improved at each time point (3.9 ± 3.1, 4.5 ± 3.1, 3.7 ± 2.5, and 5.1 ± 4.0; P < 0.01), fluorescein staining (4.3 ± 2.8) was significantly improved at each time point (2.2 ± 2.2, 1.9 ± 1.9, 1.8 ± 1.6, and 1.8 ± 1.8; P < 0.01), and RB (2.6 ± 3.0) staining was significantly improved from 6-month treatment (1.5 ± 1.9, 1.9 ± 1.9, and 1.4 ± 1.8; P < 0.05, 0.01, and 0.01, respectively). When combined with PPs, the tBUT and RB staining scores were found to be significantly improved in the AS + PP group compared with those of the AS only group. Long-term application of AS eye drops was found to be an effective and apparently safe treatment for SS dry eye. Furthermore, PPs in combination with AS eye drops were considered to have an additive effect on SS dry eye.