Co-culturing the fungal endophyte Chaetomium sp. with the bacterium Bacillus subtilis on solid rice medium resulted in an up to 8.3-fold increase in the accumulation of constitutively present metabolites that included a 1:1 mixture of 3- and 4-hydroxybenzoic acid methyl esters (1 and 2, respectively), and the polyketides acremonisol A (3), SB236050 (4), and SB238569 (5). In addition, seven compounds including isosulochrin (6), protocatechuic acid methyl ester (7), as well as five new natural products (8e12) were detected in the co-cultures, but not in axenic fungal cultures. Treatment of Chaetomium sp. with the epigenetic modifier suberoylanilide hydroxamic acid or 5-azacytidine resulted in an enhanced accumulation of 6, which was likewise detected during co-culture. Compound 5 showed strong cytotoxicity against the mouse lymphoma L5178Y cell line with an IC50 value of 1 mM, as well as weak antibacterial activity against B. subtilis with an MIC value of 53 mM.