Interleukin-6　(IL-6)　protects　neurons　by　inhibiting　the　expression　of　factors　related　to　neuronal　injury　in　nervous　headache　patients.　The　development　of　rapid　and　sensitive　IL-6　detection　methods　will　be　very　advantageous　for　easing　the　pain　of　such　patients.　In　this　work,　an　immobilization-free　immunodetection　method　is　explored　for　the　voltammetric　screening　of　IL-6　in　serum　samples　from　nervous　headache　patients.　Initially,　methylene-blue-encapsulated　liposomes　(MBLS)　labeled　with　anti-IL-6　detection　antibodies　are　confined　in　an　anti-IL-6　capture　antibody-coated　microplate　through　a　sandwich-type　immunoreaction,　and　subsequently　subjected　to　lysis　treatment.　After　that,　the　lytic　solution　is　transferred　into　a　detection　cell　including　a　Nafion-modified　working　electrode.　Methylene　blue　molecules　with　positive　charge　are　captured　on　the　negatively　charged　Nafion　membrane,　thus　generating　a　voltammetric　signal.　The　voltammetric　peak　currents　are　relative　to　the　amount　of　IL-6　in　the　solution.　Under　optimized　experimental　situations,　MBLS-based　split-type　electrochemical　sensing　protocols　have　acceptable　voltammetric　currents　for　IL-6　from　0.01　to　100　pg　mL−1,　and　allow　screening　at　a　concentration　of　IL-6　as　low　as　9.1　fg　mL−1.　The　batch-to-batch　coefficients　of　variation　were　≤11.95%.　Good　anti-interference　capability　was　achieved　against　other　biomolecules.　Seven　human　serum　specimens　and　two　diluted　serum　samples　including　IL-6　obtained　from　nervous　headache　patients　were　determined　by　MBLS-based　electrochemical　immunoassay,　and　achieved　well-matched　results　in　comparison　with　those　of　the　IL-6　ELISA　protocol.　©　2025　The　Royal　Society　of　Chemistry.