The objective of this study is to evaluate the ability of spleen volume, blood flow, and an index incorporating multiple measures to predict cirrhosis-associated hypersplenism. A total of 39 patients (14 women and 25 men; mean [± SD] age, 52 ± 10 years) with cirrhosis and sequelae of portal hypertension underwent 4D flow MRI and anatomic 3-T MRI performed before and after contrast administration. Unenhanced 4D flow MRI was used to assess abdominal hemodynamics, and splenic volumes were measured on T1-weighted gradient-recalled echo MRI. Relationships among demographic characteristics, blood component counts, splenic volume, arterial flow, venous flow, and the percentage of shunted portal flow were assessed in 29 consecutive patients (i.e., the derivation group), to develop a splenic flow index. This index was assessed along with splenic volume and blood flow alone in 10 additional consecutive patients (i.e., the validation group) via ROC curve analysis, to identify platelet counts of less than 50 × 103 cells/μL, leukocyte counts of less than 3.0 × 103 cells/μL, or both. In the derivation cohort (platelet count, 129 ± 76 × 103 cells/μL), splenic volume, arterial flow, venous flow, and the percentage of shunted portal flow were inversely correlated with platelet counts (ρ = -0.68, -0.68, -0.56, and -0.36, respectively; p < 0.05). Adding splenic volume to arterial flow and the product of venous flow and the percentage of shunted portal flow indexed to the body surface area yielded superior correlations with platelet counts, leukocyte counts, and the degree of severity of hypersplenism (ρ = -0.75, -0.48, and -0.75, respectively; p ≤ 0.001) and predicted severe hypersplenism (sensitivity, 100%; specificity, 100%) in the validation cohort (platelet count, 93 ± 71 × 103 cells/μL). A splenic flow index that incorporates both splenic volume and blood flow is a better indicator of hypersplenism than is splenic volume alone.