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The physicochemical and biochemical changes during the fermentation of four clones and two native varieties of Theobroma cacao L. were studied. Fermentation was performed in traditional wood cubes. During fermentation, the cotyledon pH decreased, and the temperature increased to more than 10 °C above the ambient temperature (47 °C). The fermentation index (FI) increased in the clones C1, C4, C8, C9, and Guayaquil (G) to close to one at 120 h of fermentation. For the FI of the cocoa Criollo (Cr), a value of 2.5 was proposed according to the spectrophotometric scan performance. The total polyphenol content increased in all the samples from 21 (C8) to 70 (Cr) % in a comparison of the TPC at T0 and T120, respectively. The total flavonoid content increased from 16 (C8) to 51% in Guayaquil (G) during the fermentation period. In the case of the methylxanthines, such as theobromine and caffeine, both quantities decreased. The theobromine content decreased in all the samples from 6 (G) to 31% (C8). The caffeine content decreased in all the samples from 3% in Cr to 25% in C1 and G after fermentation. The antioxidant capability did not change after 120 h of fermentation, and the amount of methylxanthines did not affect the antioxidant potential of the fermented cocoa. The FTIR scan of the fat-free cocoa showed significant differences between the unfermented and fermented beans, and several peaks assigned to carbohydrates and proteins decreased.