Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and the absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival was significantly lower in patients with the absolute monocyte counts ≥0.51 109/L (87.8% vs. 96.4%, P<0.001). It was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46, 95% confidence intervals 1.05-5.75, P=0.039). These results suggested the absolute monocyte counts at diagnosis is an independent significant risk factor for central nervous system relapse in patients with diffuse large B-cell lymphoma.