Purpose To analyze a single center's experiences with ocriplasmin on vitreomacular traction (VMT) and the rate of VMT release, full-thickness macular hole (full-thickness MH) closure, and best-corrected visual acuity (BCVA) changes. Design Retrospective interventional case series. Methods Single-center study of 58 eyes of 56 patients who received intravitreal ocriplasmin for VMT with or without full-thickness MH. VMT release, full-thickness MH closure, visual acuity changes, and anatomic characteristics on spectral-domain optical coherence tomography (SD OCT) were analyzed. Results VMT resolved in 29 of 58 eyes (50%) and nonsurgical closure of full-thickness MH was achieved in 4 of 15 eyes (27%). Mean logMAR BCVA among all treated eyes improved from 0.51 (20/65) at baseline to 0.36 (20/46) at final follow-up (P =.0018) with mean follow-up of 8.7 months. When compared to eyes without VMT release, eyes with successful vitreomacular release had a better pretreatment BCVA (20/48 vs 20/89, P =.004) and final follow-up BCVA (20/31 vs 20/68, P =.0001). Improvement in BCVA was significant in eyes with VMT release (P =.0001). Transient ellipsoid zone changes were noted in 26% of treated eyes (n = 15), of which 14 had successful VMT release. Transient subfoveal fluid accumulation was noted in all these patients with vitreomacular release. Mean time to resolution of ellipsoid zone changes was within 38 days. Conclusion In clinical practice, intravitreal injection of ocriplasmin achieved VMT release in approximately one half of treated eyes, with a 27% closure rate for full-thickness MH. Transient ellipsoid changes were evident in 26% of treated eyes, more common in eyes with successful VMT release.