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Background Rilpivirine-based regimens are now preferred or alternative first-line regimens according to many HIV treatment guidelines. Recently, a surveillance study conducted in Argentina determined that prevalence of pre-treatment resistance to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) was 10%. The aim of this study was to analyse the prevalence of resistance mutations to newer generation NNRTIs in the population starting ART in Argentina.Methods We analysed the prevalence of resistance mutations to rilpivirine and etravirine (according to the IAS list), obtained through a nationally representative pre-treatment HIV-drug resistance (PDR) surveillance study performed in Argentina in 2014-2015. Briefly, 25 ART-dispensing sites throughout the country were randomly chosen to enrol 330 adults starting ART. Samples were processed with Trugene (Siemens)® and analysed using the Stanford algorithm.Results All 270 samples corresponding to participants with no prior exposure to antiretroviral drugs were included in this analysis. Median (IQR) age was 35 years (28–43); 66.7% were male; median (IQR) CD4+T-cell count was 284 cells/mm3(112–489). The prevalence of resistance to any antiretroviral was 16% (±5%) and prevalence of NNRTI RAMs was 13% (±4%). The prevalence of resistance to rilpivirine was 8% (±3%). Prevalence of resistance to etravirine was 4% (±3%). The most frequent mutations conferring resistance to rilpivirine were: E138A (n=6) and G190A (n=4).Conclusions This PDR surveillance study showed concerning levels of HIV drug resistance (HIVDR) in Argentina, not only for first-generation NNRTIs but also to rilpivirine. In our setting, performing resistance testing would be necessary before prescription of ART even if a second-generation NNRTI-based regimen was used as first-line therapy.