INTRODUCTION: The aminoglycoside antibiotics gentamicin and geneticin (G418) can both cause nephrotoxicity at high concentrations. Specifically, gentamicin causes renal cell death via oxidative stress and endoplasmic reticulum (ER) stress (Quiros et al., 2011) whereas geneticin primarily causes ER stress via modification of intracellular proteins (Jin et al., 2004). Caffeic acid is a polyphenol antioxidant which can be derived from the diet and has recently been shown to reduce gentamicin nephrotoxicity in rats (Aygün et al., 2012). AIMS: The aims of this study were (i) to compare the toxicity of both gentamicin and geneticin on renal epithelial proximal tubular cells and (ii) to investigate the effects of the hydroxycinnamate caffeic acid on aminoglycoside toxicity. The effects of caffeic acid on these aminoglycosides were compared with its effects on paraquat – a recognised pro-oxidant and inducer of ER stress (Samai et al., 2007, Chinta et al., 2008). METHODS: Confluent cultures of a rat proximal tubular cell-line (NRK-52E cells) were dosed once daily for 72 hours with sub-lethal concentrations of gentamicin (10 mg/mL) or geneticin (1 mg/mL) in the absence or presence of caffeic acid (0.5 mM). NRK-52E cells were also incubated with paraquat (5 mM) for 24 hours with or without caffeic acid (0.5 mM). The 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium (MTT) assay was used to measure cell viability. Data are presented as mean % cell viability±S.D. analysed using one-way ANOVA followed by Bonferroni’s post-test. RESULTS: Gentamicin (GENT) produced a significant reduction in the viability of NRK-52E cells at a concentration of 10 mg/mL (untreated cells: 100.0±3.8% vs. GENT only: 38.9±14.3%, p<0.05, n=6). Geneticin (G418) also produced a significant reduction in cell viability at a concentration of 1 mg/mL (untreated cells: 100.0±3.8% vs. GENT only: 24.8±5.1%, p<0.05, n=6). Caffeic acid (CA) did not affect gentamicin toxicity (GENT only: 38.9±14.3% vs. GENT+CA: 33.5±17.0%, p>0.05, n=6) however, it was able to reduce geneticin toxicity significantly (G418 only: 24.8±5.1% vs. G418+CA: 35.8±7.6%, p<0.05, n=6). Paraquat (PQ) also produced a significant reduction in NRK-52E cell viability at a concentration of 5 mM (untreated cells: 100.0±3.4% vs. PQ only: 12.6±6.3%, p<0.05, n=6). Caffeic acid reduced paraquat toxicity significantly (PQ only: 12.6±6.3% vs. PA+CA: 24.2±4.4%, p<0.05, n=6). Caffeic acid only (0.5 mM) did not have any effect on the viability of NRK-52E cells (data not shown). CONCLUSIONS: These results suggest that caffeic acid has a differential effect on aminoglycoside toxicity which requires further study. As it was able to reduce renal cell toxicity produced by geneticin and paraquat significantly, the possible effect of caffeic acid on ER stress pathways within these cells warrants further investigation.