The oil palm (Elaeis guineensis) is the highest yielding crop in the world. The fruit is a drupe whose thick fleshy mesocarp is exceptionally rich in oil (80% dry mass). Many studies have focused on the biochemical and dynamic changes of mRNA levels of oil palm fruit ripening and this study focuses on profiling of mesocarp proteins using two-dimensional gel electrophoresis (2-DGE) and mass spectrometry approaches. Oil palm fruits were collected at various stages starting 10 week after anthesis (WAA) to complete ripe stage of 20 WAA. Total proteins were extracted using TCA-acetone precipitation and individual proteins were separated by 2-DGE. In this study, changes in the oil palm mesocarp proteins expression between 18 and 20 WAA were reported. More than 60% of up- and down-regulated proteins were successfully identified and majority of the proteins were linked to carbohydrate, amino acid and xenobiotics metabolisms. Fewer proteins related to energy, lipid, secondary; and cofactors and vitamins metabolisms. Further analysis is being conducted for a better understanding on the regulatory mechanisms that function during the maturation and ripening in the oil-rich mesocarp.