PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Overall, 105 (10%) of 1,012 patients tested harbored PIK3CA mutations. Sixty-six (median 3 prior therapies) of the 105 PIK3CA-mutant patients, including 16 individuals (of 55 PIK3CA-mutant patients tested) with simultaneous KRAS mutations, were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor; 17% (11/66) achieved a partial response (PR). Patients with a PIK3CA H1047R mutation compared with patients who had other PIK3CA mutations or patients with wild-type PIK3CA treated on the same protocols had a higher PR rate (6/16, 38% vs. 5/50; 10% vs. 23/174, 13%, respectively; all P ≤ 0.02). None of the 16 patients with coexisting PIK3CA and KRAS mutations in codon 12 or 13 attained a PR (0/16, 0%). Patients treated with combination therapy versus single-agent therapies had a higher PR rate (11/38, 29% vs. 0/28, 0%; P = 0.002). Multivariate analysis showed that H1047R was the only independent factor predicting response [OR 6.6, 95% confidence interval (CI), 1.02-43.0, P = 0.047). Our data suggest that interaction between PIK3CA mutation H1047R versus other aberrations and response to PI3K/AKT/mTOR axis inhibitors warrants further exploration.