Pre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2-9%) or higher (≥10%) frequencies during efavirenz- vs. nevirapine-ART.We conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA ≥400 copies/mL at month-12 of ART, was compared by PDR genotypes.PDR was detected in 59/1231 (4·8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69·2% (27/39) vs. wild-type 10·4% (70/674); p = 0·0001], whether detected as minority [66·7% (4/6)] or higher [69·7% (23/33)] frequencies in an individual's HIV quasispecies (p = 0·002 and p < 0·0001, respectively), or mutations at single [50·0% (12/24)] or multiple [100·0% (15/15)] codons (p < 0·0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25·0% (5/20) vs. wild-type 5·0% (25/498); p = 0·005], but only if detected at multiple drug-resistant codons [50·0% (3/6); p = 0·003] or high frequencies PDR [33·3% (5/15); p = 0·001].The risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz- compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings.NIH, PEPFAR.