BACKGROUND: In HIV-infected patients, prediction of Cytomegalovirus (CMV) disease remains difficult. A protective role of mannan-binding lectin (MBL) and ficolins against CMV disease has been reported after transplantation, but the impact in HIV-infected patients is unclear. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we investigated associations between plasma levels of MBL/ficolins and CMV disease. We compared HIV-infected patients with CMV disease (cases) to CMV-seropositive patients without CMV disease (controls) matched for CD4 T-cells, sampling time, and use of combination antiretroviral therapy. MBL and M-ficolin, L-ficolin, and H-ficolin were quantified using ELISA. RESULTS: We analysed 105 cases and 105 matched controls. CMV disease was neither associated with MBL (odds ratio [OR] 1.03 per log(10) ng/mL increase (95% CI 0.73-1.45)) nor with ficolins (OR per log(10) ng/mL increase 0.66 (95% CI 0.28-1.52), 2.34 (95% CI 0.44-12.36), and 0.89 (95% CI 0.26-3.03) for M-ficolin, L-ficolin, and H-ficolin, respectively). We found no evidence of a greater association between MBL and CMV disease in patients with low CD4 counts; however in the multivariable analysis, CMV disease was more likely in patients with an increased HIV RNA (OR 1.53 per log(10) copies/mL; 95% CI 1.08-2.16), or a shorter duration of HIV-infection (OR 0.91 per year; 95% CI 0.84-0.98). CONCLUSIONS: CMV disease is not associated with low levels of MBL/ficolins, suggesting a lack of a protective role in HIV-infected patients.