Background: Somatic mutations in IDH1 or IDH2 genes are prevalent in diverse solid tumors and implicated in tumorigenesis. Therapeutic responses to IDH inhibitors are infrequent plausibly due to presence of simultaneous alterations activating compensatory molecular pathways. Methods: We retrospectively reviewed results from clinical genomic profiling with targeted next-generation sequencing in two independent data sets of archival formalin-fixed paraffin-embedded (FFPE) tumor samples (Ion Torrent < 50 genes, 300; FoundationOne < 343 genes, 30; Oncomine 128 genes, 4) and plasma liquid biopsies (Guardant360 < 73 genes panel, 337 samples) from patients with solid tumors of all stages. Results: In 334 FFPE samples the most represented cancers were gliomas (50%), melanomas (14%), cholangiocarcinomas (11%), and non-small cell lung cancer (NSCLC, 6%). In 296 IDH1-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (45%), BRAF (11%), KRAS (9%), and PIK3CA (26, 9%). In the most represented IDH1-mutated tumor types commonly altered genes were TP53 (66%) in gliomas, BRAF (53% [V600K/R 30%, V600E 19%]) in melanomas, PIK3CA (13%), CDKN2A (13%) in cholangiocarcinomas and KRAS (65%) in NSCLC. In 38 IDH2-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (32%), and KRAS (16%). In 337 plasma samples the most represented cancers were NSCLC (39%), cholangiocarcinoma (13%), and breast cancer (8%). In 172 IDH1-mutated plasma samples the most frequent simultaneous alterations were in TP53 (40%), KRAS (23%), EGFR (16%) and BRAF (16%). In the most represented IDH1-mutated tumors commonly altered genes were TP53 (48%), KRAS (37%) in NSCLC and TP53 (37%), KRAS (24%), BRAF (18%) in cholangiocarcinoma. In 161 IDH2-mutated plasma samples the most frequent simultaneous alterations were in TP53 (43%), EGFR (20%), and KRAS (19%). In the most represented IDH2-mutated tumors commonly altered genes were TP53 (43%), EGFR (32%), KRAS (18%) in NSCLC and TP53 (18%), ESR1 (18%), KRAS (18%) in breast cancer. There were 4 tumors with IDH1 and IDH2mutations. Conclusions:IDH1 and IDH2 mutations often coexist with simultaneous oncogenic alterations including these in potentially druggable molecular targets.