Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been recently reported in 23% of a large series of classic CS. Here, we validated our small (n = 10) pilot study in a large patient series that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% (49/608) of PTEN mutation-negative CS and CS-like (CSL) individuals (SDH^var+). None of these SDHx variants was found in 700 population controls (P < 0.0001). We then found that SDHx variants also occur in 6% (26/444) of PTEN mutation-positive (PTEN^mut+) CS/CSL individuals (PTEN^mut+/SDH^var+). Of 22 PTEN^mut+/SDH^var+ females, 17 had breast cancers compared with 34/105 PTEN^mut+ (P < 0.001) or 27/47 SDH^var+ patients (P = 0.06). Notably, individuals with SDH^var+ alone had the highest thyroid cancer prevalence (24/47) compared with PTEN^mut+ patients (27/105, P = 0.002) or PTEN^mut+/SDH^var+ carriers (6/22, P = 0.038). Patient-derived SDH^var+ lymphoblastoid cells had elevated cellular reactive oxygen species, highest in PTEN^mut+/SDH^var+ cells, correlating with apoptosis resistance. SDH^var+ cells showed stabilized and hyperactivated hypoxia inducible factor (HIF)1α signaling. Most interestingly, we also observed the loss of steady-state p53 in the majority of SDH^var+ cells. This loss of p53 was regulated by MDM2-independent NADH quinone oxidoreductase 1-mediated protein degradation, likely due to the imbalance of flavin adenine dinucleotide/nicotinamide adenine dinucleotide in SDH^var+ cells. Our data suggest the potential regulation of HIF1α, p53 and PTEN signaling by mitochondrial metabolism in CS/CSL tumorigenesis. Together, our findings suggest the importance of considering SDHx as candidate predisposing and modifier genes for CS/CSL-related malignancy risks, and a mechanism which suggests ways of therapeutic reversal or prevention.