Abstract Background The myeloid differentiation primary response gene (MYD88) mutation in primary central nervous system lymphomas (PCNSL) may be associated with unfavorable prognosis; however, current evidence remains limited. We aimed to characterize PCNSLs by integration of clinicopathological, molecular, treatment, and survival data. Methods We retrospectively identified and validated 57 consecutive patients with PCNSLs according to the 2017 WHO classification of lymphoid neoplasms over 13 years. Formalin-fixed paraffin-embedded tumor samples underwent polymerase chain reaction assay to detect MYD88 mutation. We used Cox regression for survival analysis, including age, treatment, and MYD88 as covariates. We searched the literature for studies reporting demographics, treatment, MYD88, and survival of PCNSL patients and incorporated individual patient data into our analyses. Results The median age was 66 years and 56% were women. All 57 patients had PCNSL of non-germinal center cell subtype and the majority (81%) received either single or combined therapies. There were 46 deaths observed over the median follow-up of 10 months. MYD88 mutation status was available in 41 patients of which 36 (88%) were mutated. There was an association between MYD88 mutation and better survival in the multivariable model (hazard ratio [HR] 0.277; 95% confidence interval [CI]: 0.09-0.83; P = .023) but not in a univariable model. After incorporating additional 18 patients from the literature, this association was reproducible (HR 0.245; 95% CI: 0.09-0.64; P = .004). Conclusions Adjusting for confounders, MYD88-mutant PCNSL appears to show improved survival. While further validation is warranted, detection of MYD88 mutation will aid the identification of patients who may benefit from novel targeted therapies.