Chemotherapy-based treatment of patients with primary central nervous system lymphoma can lead to durable remissions and potentially cure in a fraction of patients. Accurate assessment of residual disease is necessary to determine the duration and success of treatment that cannot be achieved by contrast-enhanced imaging due to limited sensitivity and specificity. A tumor-derived blood-based biomarker, if detectable and quantifiable, could serve as a more specific and reliable marker for these patients. The goal of this study was to assess whether lymphoma-specific IgH rearrangements can be detected in plasma of patients with PCNSL. PCNSL tissue was analyzed by capturing and sequencing the IgH genomic regions (IgCap) using next generation sequencing with the Illumina platform. Plasma of patients with detected IgH rearrangement was then analyzed for presence of the respective rearrangement using polymerase chain reaction. Tumor tissue and matched plasma of five treatment-naïve patients with biopsy-proven PCNSL (mean age of 65.6 years; range 62-68 years) were analyzed. All patients had measurable contrast-enhancing disease on MRI at time of plasma collection. IgH rearrangements were identified in 4 of 5 analyzed PCNSL tissue samples. The respective rearrangement could be detected in the plasma of 1 patient (25 %) but not in the others. IgH rearrangements can be detected in tumor tissue of patients with PCNSL using IgCap, however, they are absent or only present in minimal quantities in plasma, even in treatment-natïve patients with bulky disease. Alternative strategies to develop circulating biomarkers for PCNSL patients need to be explored.