Using two-dimensional difference gel electrophoresis (2D DIGE) we have analyzed monocytes derived from 10 sickle cell disease patients (5 males and 5 females ages 12-18) to generate hypotheses regarding signature proteins that appear most positively and negatively correlated with vasoocclusive event rate. Signature proteins have been identified by tandem mass spectrometry. Based on the limited number of samples analyzed, the most negatively correlated proteins related to crises rate were transketolase and coronin in the membrane fraction and heat shock 70 kDa protein cognate 4, and adenylate kinase isoenzyme 2, mitochondrial found in the cytosolic fraction. The protein spots that were most positively correlated with crisis rate in the cytoplasmic fraction were far upstream element-binding protein and Alpha actinin 1 or Alpha actinin 4. Utilizing StepSIM analysis, vinculin was able to classify all samples from the combined set and the membrane-only set, and cytosolic leukotriene A-4 hydrolase and phosphoglycerate kinase were also identified as important indicators for differentiating between low and high vasoocclusive event rates.