Nemorosone is a polycyclic polyisoprenylated benzophenone (PPBs) with strong cytotoxic activity. It is the major constituent of Clusia rosea floral resin and brown Cuban propolis. Other PPBs found in Cuban propolis are oxidized and cyclized derivatives of nemorosone. The instability of PPBs carrying an enolizable 1,3-diketone system has been suggested, and the elucidation of this aspect is very fundamental for the evaluation of their biologic activity. Electrospray ionization multistage tandem mass spectrometry (ESI-MS(n)) was employed to shed light on the origin of these derivatives of nemorosone and to define the stability of this natural product. For this purpose, we initially performed MS(n) experiments on seven related PPBs to obtain useful information for structural characterization of this class of compounds and to identify the degradation products of nemorosone. The proposed fragmentation pathways, supported by exact mass measurements, allowed the nature of side chains on the bicyclo core and the type and position of their modifications to be established. In a second part, the degradation profile of nemorosone under different conditions was investigated to assess the possible effects of isolation procedures, climatic, and storage conditions on its stability. Our results reveal that nemorosone undergoes rapid degradation in n-hexane and chloroform solutions. The degradation products, identified by HPLC-ESI/MS(n) and NMR, are identical to derivatives of nemorosone previously isolated from propolis and plants. Thus, these PPBs are artefacts formed predominantly during the extraction and purification procedures.