<b><i>Aim:</i></b> Evaluate the real-life experience with ocriplasmin on vitreomacular traction (VMT) release and full-thickness macular hole (FTMH) closure in Portugal. <b><i>Methods:</i></b> Multicentric, retrospective study of 83 eyes of 78 patients who were treated with intravitreal ocriplasmin for VMT with and without FTMH. Primary outcomes were VMT release and FTMH closure. Secondary outcomes included visual acuity changes and structural features on spectral-domain ocular coherence tomography. <b><i>Results:</i></b> VMT resolved in 47 of the 83 eyes (56.6%) and 6 of the 12 FTMH were closed (50.0%). Mean best-corrected visual acuity (BCVA) improved from 65.1 at baseline to 70.8 ETDRS letters at the end of follow-up (p < 0.0001) with a mean follow-up of 138.8 days. Improvement in BCVA was significantly better in eyes with VMT release (p = 0.021). Approximately 73% of patients had normal ellipsoid zone integrity at the end of follow-up, 87% had no neurosensorial detachment and 40% had no intra- or subretinal fluid. <b><i>Conclusion:</i></b> VMT release and FTMH closure were achieved in more than half of the treated eyes and were correlated with significant BCVA improvements and favorable baseline characteristics. In fact, if a careful patient selection is carried out, VMT resolution with ocriplasmin can be optimized, tailoring the best approach to each patient.