Objective The aim of this study was to evaluate first-trimester maternal characteristics and biomarkers in pregnancies that subsequently develop HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Method Maternal history, biochemical, and biophysical parameters were compared between women who developed HELLP, preeclampsia (PE) without HELLP and controls. After determination of significant variables through univariate analysis a first-trimester prediction model was obtained by applying logistic regression analysis. Performance of the model was evaluated. Results Twenty participants with HELLP were compared with 147 patients that developed PE without HELLP and 2810 controls. Women with HELLP were more likely Caucasian, nulliparous and presented a higher mean arterial pressure (MAP) when compared with controls. As opposing to women who developed HELLP, women who developed PE without HELLP were more likely of African-American origin and presented an even higher first-trimester MAP. Enrollment biochemical and biophysical parameters were similar between HELLP and PE or controls. Ethnicity, nulliparity, history of previous PE, history of previous HELLP syndrome, and first-trimester MAP were primary risk factors. A prediction rule for HELLP syndrome had an area under the curve of 0.80, with 75% sensitivity for 79% specificity. Conclusion The majority of pregnancies that develop HELLP syndrome can be predicted in the first trimester. (C) 2015 John Wiley & Sons, Ltd.