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Background  Current World Health Organization guidelines for conducting anti-malarial drug efficacy clinical trials recommend genotyping  Plasmodium falciparum  genes  msp1  and  msp2  to distinguish recrudescence from reinfection. A more recently developed potential alternative to this method is a molecular genotyping assay based on a panel of 24 single nucleotide polymorphism (SNP) markers.    Methods  Performance parameters of these two genotyping methods were compared using data from two recently completed drug efficacy trials. Blood samples from two anti-malarial therapeutic trials were analysed by both  msp  genotyping and the 24 SNP assay. Additionally, to conserve time and resources, the statistical program R was used to select the most informative SNPs for a set of unrelated Malawian samples to develop a truncated SNP-based assay for the region surrounding Blantyre, Malawi. The ability of this truncated assay to distinguish reinfection from recrudescence when compared to the full 24 SNP assay was then analysed using data from the therapeutic trials.    Results  A total of 360 samples were analysed; 66 for concordance of  msp  and SNP barcoding methodologies, and 294 for assessing the most informative of the 24 SNP markers. SNP genotyping performed comparably to  msp  genotyping, with only one case of disagreement among the 50 interpretable results, where the SNP assay identified the sample as reinfection and the  msp  typing as recrudescence. Furthermore, SNP typing was more robust; only 6% of samples were uninterpretable by SNP typing, compared to 19.7% when  msp  genotyping was used. For discriminating reinfection from recrudescence, a truncated 6 SNP assay was found to perform at 95.1% the accuracy of the full 24 SNP bar code.    Conclusions  The use of SNP analysis has similar sensitivity to the standard  msp  genotyping in determining recrudescence from reinfection. Although more expensive, SNP typing is faster and less work intensive. Limiting the assay to those SNPs most informative in the geographical region of interest may further decrease the workload and the cost, making this technique a feasible and affordable alternative in drug efficacy trials.    Electronic supplementary material  The online version of this article (10.1186/s12936-019-2695-0) contains supplementary material, which is available to authorized users.

Comparison of msp genotyping and a 24 SNP molecular assay for differentiating Plasmodium falciparum recrudescence from reinfection