Non-coding RNA molecules, particularly miRNA, regulate translation of mRNA and have been found to target expression of genes important in immune response, such as IFN-γ. Differences in blood transcriptome signatures and differential miRNA expression have been reported to discriminate between uninfected, active and latent tuberculosis. We analysed the ability of small RNA molecules (0–150 nucleotides) in blood plasma to act as biomarkers of tuberculosis treatment response. Total blood plasma small RNA (0–150 nucleotides) concentration was significantly higher (p < 0.0001) in 31 individuals before therapy (median 332pg μL-1 plasma, range 93–1603pg μL-1) than at the end of therapy at week 24 (median 86pg μL-1 plasma, range 16–1098pg μL-1). Expression analysis of small RNA genes revealed that, in 5 tuberculosis-infected HIV-1 negative individuals, 36 of 90 genes (> 2-fold, p < 0.05) were upregulated before compared to post-therapy completion. Hsa-miR-19b, 29a, 17–3p, 133a, small RNA concentration and SNORD61 were further tested and this analysis revealed that in 84% of individuals (n = 31) at least one of these biomarkers was upregulated > 2 fold in active tuberculosis. Co-infection with HIV-1 was not found to change the expression of these six tested biomarkers.