BACKGROUND Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis. AIM To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases. METHODS A nested case-control study utilizing a large computerized database. Cirrhosis cases (n = 5258) were compared to controls (n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated. RESULTS The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who's PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35). CONCLUSION In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.