The genus Ganoderma has been little studied in arid areas worldwide. Ganoderma subincrustatum and Ganoderma weberianum strains were obtained from the Sonoran Desert, Sonora, Mexico. Ganoderma spp. synthesize triterpenoids such as ganoderic acids with antiproliferative activity because they inhibit specific targets, induce apoptosis, and increase the activity of killer cells. Mycelium and fruiting body chloroform extracts from G. subincrustatum and G. weberianum were tested on HeLa, A549, L-929, and RAW 264.7 cell lines. Extracts from the fruiting body present higher antiproliferative activity than mycelium. All extracts induced vesicle and cellular debris formation in all cell lines, being non-selective for cancerous cells. Chloroform extract from G. subincrustatum fruiting bodies presented higher activity against all cell lines. Fractions F7 and F15 from this extract exhibited an IC50 of 37.9 and 41.9 mu g/mL on the A549 cell line, respectively; however, chloroform crude extract showed higher activity (IC50 of <25 g/mL) in all cell lines. Flow cytometry assays of F7 revealed cell death by apoptosis in A549 cells. NMR suggested the presence of ganoderic acids in F7. In future research, it will be interesting to characterize these fractions (metabolites, their bioactivities, and mechanism of action).