BACKGROUND The subtype A variant in the Former Soviet Union (A(FSU)) causes most of Russia's HIV-1 infections. However, the spectrum of drug-resistance mutations (DRMs) in antiretroviral experienced patients with this variant has not been studied. METHODS Between 2010 and 2013, genotypic resistance testing was performed on plasma samples from 366 antiretroviral-experienced patients in Siberia. RESULTS Three-hundred patients (82%) had subtype A(FSU) and 55 (15%) had CRF02_AG viruses. The pattern of DRMs was consistent with patient antiretroviral history with one exception. G190S was the most common nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutation, occurring in 55 (33%) subtype A(FSU) viruses from 167 NNRTI-experienced patients compared with none of 37 CRF02_AG viruses from NNRTI-experienced patients (P < 0.001). The next most common subtype A(FSU) NNRTI-resistance mutation, K103N, occurred in 25 (15%) viruses. Wild-type glycine (G) at position 190 is encoded by GGC in more than 99% of published A(FSU) strains. By contrast, G190 is encoded by GGA or GGG in 97% of other subtypes and in subtype A strains outside of the FSU. Therefore, G190S results from a single G→A transition: G (GGC) → S (AGC) almost exclusively in subtype A(FSU) viruses. CONCLUSIONS The predisposition of subtype A(FSU) to G190S is concerning because G→A is the most common HIV-1 mutation and because G190S causes higher levels of nevirapine and efavirenz resistance than K103N. This study exemplifies the need for characterizing the genetic mechanisms of resistance in diverse populations and warrants studies to verify that NRTI/NNRTI regimens are as efficacious in treating subtype A(FSU) as viruses belonging to other subtypes.