While primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML) is the most common orbital tumor, there are large gaps in knowledge of its natural history. We conducted a retrospective analysis of the largest reported cohort, consisting of 182 patients with POAML, diagnosed or treated at our institution to analyze long-term outcome, response to treatment, and incidence and localization of relapse and transformation. The majority of patients (80%) presented with stage I disease. Overall, 84% of treated patients achieved a complete response after first-line therapy. In patients with stage I disease treated with radiation therapy (RT), doses ‡30.6 Gy were associated with a significantly better complete response rate (P 5 .04) and progression-free survival (PFS) at 5 and 10 years (P < .0001). Median overall survival and PFS for all patients were 250 months (95% confidence interval [CI], 222 [upper limit not reached]) and 134 months (95% CI, 87-198), respectively. Kaplan-Meier estimates for the PFS at 1, 5, and 10 years were 91.5% (95% CI, 86.1% to 94.9%), 68.5% (95% CI, 60.4% to 75.6%), and 50.9% (95% CI, 40.5% to 61.6%), respectively. In univariate analysis, age >60 years, radiation dose, bilateral ocular involvement at presentation, and advanced stage were significantly correlated with shorter PFS (P 5 .006, P 5 .0001, P 5 .002, and P 5 .0001, respectively). Multivariate analysis showed that age >60 years (hazard ratio [HR] 2.44) and RT<30.6Gy (HR54.17) were the only factors correlated with shorter PFS (P 5 .01 and P 5 .0003, respectively). We demonstrate that POAMLs harbor a persistent and ongoing risk of relapse, including in the central nervous system, and transformation to aggressive lymphoma (4%), requiring long-term follow-up.