Early prediction of lactation persistency will potentially be an important management tool influencing decisions on reproduction and feeding management. Primiparous cows have a relatively stable and high persistency while it is quite variable for multiparous cows. Therefore, the objective was to predict multiparous cows’ lactation persistency, within the first 6 weeks of lactation, based on two or three variables. The dataset used contained 19 production data and blood biomarkers of 36 multiparous Holstein cows managed for extended lactation (insemination at 8 months) with access to a milking unit. The persistency was calculated as the ratio of total milk produced during a defined period of 100 days (P1: from 100 to 200 days, P2: from 200 to 300 days, or P3: from 300 to 400 days) over the first 100 days of production (Method 1); as the quantity of milk produced at day 100, 200, 300, or 400 over the quantity produced at day 60 of lactation (Method 2); and as the slope of the smoothed milk yield curve at day 100, 200, 300, and 400 (Method 3). For each method, the cows were divided into 3 groups (12 cows per group) with a low, medium or high persistency. A clustering method (k=3) was then applied on a pair or trio among the data measured at week 1, 3, or 5. Using a trio of variables to predict persistency only improved the maximum accuracy of 3.7% (average over the methods, weeks and periods) compared to a pair of variables, and the highest accuracy obtained with a pair of variables varied from 43 to 70%. With a pair of variables, the highest accuracy was obtained with Method 1, considering milk yield and lactose in milk measured at week 1 to predict the persistency over P3. The second best pair belonged to Method 3 and involved dry matter intake and milking frequency measured at week 5 to predict persistency over P1. To conclude, Method 1 gave the highest accuracies and with this specific data set, a pair of variables in early lactation may be used to predict the persistency of the lactation at different stages of the lactation with a moderate accuracy.