Hepatocellular　carcinoma　(HCC)　is　a　highly　lethal　malignant　tumor　evolved　from　cirrhosis.　It　is　quite　significant　to　seek　accurate,　easy　markers　for　early　warning　and　diagnosis　of　HCC.　Through　prospective　cohort　follow-up　study　and　mass　spectrometry,　we　discovered　and　verified　a　serum　marker　valuable　for　early　warning　and　diagnosis.　Follow-up　observation　was　performed　on　cirrhosis　patients.　Matrix-assisted　laser　desorption/ionization　time-of-flight　mass　spectrometry　(MALDI-TOF　MS)　was　adopted　to　detect　the　serums　of　patients,　and　the　serum　polypeptides　with　a　potential　value　in　early　HCC　warning　and　diagnosis　were　screened.　Electrospray　ionization　quadrupole　time-of-flight　tandem　mass　spectrometry　(ESI-Q-TOF-MS/MS)　was　exploited　to　identify　these　screened　polypeptides.　Moreover,　the　serum　marker　concentration　was　determined　by　ELISA　to　validate　the　clinical　value　of　the　serum　marker.　Among　109　cirrhosis　patients　followed　up　for　two　years,　29　patients　(26.6%)　finally　progressed　into　HCC.　MALDI-TOF　MS　shows　that　the　concentration　of　a　3155.66Da　polypeptide　was　significantly　different　between　the　patients　that　progressed　into　HCC　and　those　not.　Through　MS/MS　identification,　it　is　confirmed　that　the　polypeptide　is　inter-alpha-trypsin　inhibitor　heavy　chain　4　(ITIH4).　The　serum　ITIH4　concentrations　in　two　groups　were　measured　with　ELISA　and　compared　with　Alpha-fetoprotein　(AFP).　Results　show　that　serum　ITIH4　and　AFP　concentrations　were　negatively　correlated　(r=-0.263,　p=0.0006),　and　the　ITIH4　concentration　had　a　significant　intergroup　difference　(p=0.000).　Receiver　operating　characteristic　(ROC)　curve　indicates　that　its　predictive　value　(area　under　the　curve,　AUC)　is　0.667,　superior　to　AFP.　For　the　patients　progressing　into　HCC,　serum　samples　were　separately　collected　when　they　were　recruited　and　diagnosed　as　cirrhosis.　Measurement　on　these　samples　reveals　that　ITIH4　was　declining　during　the　progression　of　HCC　(p=0.006).　By　virtue　of　mass　spectrometry,　we　discovered　and　identified　a　biomarker　valuable　for　early　HCC　warning　and　diagnosis.　This　marker　overperforms　the　commonly　used　AFP,　demonstrating　a　bright　prospect.