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Purpose: Effectiveness of ocriplasmin for vitreomacular traction (VMT) varies depending on the presence of common ocular conditions and patient selection criteria. We carried out a systematic literature review and meta‐analysis of ocriplasmin studies conducted in real‐world settings (RWS) and compared outcomes with those from randomized controlled trials (RCTs). Methods: We included prospective and retrospective studies from RWS documenting effectiveness of ocriplasmin in patients with VMT with or without MH, and RCTs of ocriplasmin versus control. Key end‐points were vitreomacular adhesion resolution (VMAR), nonsurgical MH closure, need for vitrectomy and safety. We conducted meta‐regression on pooled results to evaluate effects of baseline covariates and study design on outcomes. Results: Thirty RWS (2402 patients) and 5 RCTs (737 patients) were included epiretinal membrane (ERM) and broad VMA were more prevalent in RCTs. Primary VMAR, vitrectomy and MH closure rates were comparable between RWS and RCTs. Rates of nsVMAR were significantly higher in RWS than RCTs (odds ratio 1.66; 95% confidence interval [CI]: 1.18–2.34). nsVMAR rates were inversely associated with ERM prevalence (odds ratio 0.20; 95% CI: 0.08–0.51). Compared with the recent OASIS trial, RWS reported a higher incidence of new/worsening subretinal fluid cases and less photophobia, photopsia, vitreous floaters, electroretinogram abnormalities and MH progression. Conclusions: Ocriplasmin was significantly more effective in achieving nsVMAR in RWS than in RCTs. Lower ERM prevalence in RWS was the single significant explanatory variable for this difference. Conclusions on ocriplasmin safety in RWS are limited due to inconsistent reporting. [ABSTRACT FROM AUTHOR]