Oxidative stress has become the focus of interest as a potential cause of male infertility. We evaluate effects of lipoic acid (LA) supplementation on glutathione S-transferase (GST) expression. This randomized, triple-blind, placebo-controlled clinical trial was conducted on 44 infertile males with idiopathic asthenozoospermia. Men were randomized to receive 600 mg LA or placebo once daily for 12 weeks and semen samples and venous blood samples were obtained. GST expression, reactive oxygen species (ROS) levels, GST activity and reproductive hormone profiles were also measured. GST expression in the intervention group were significantly higher than the control group. Also, at the end of the study, GST activity increased, and ROS levels decreased significantly compared to the baseline. Additionally, the intervention group showed an increase in testosterone and decrease in serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin after 12 weeks, but this difference was not significant. We conclude a 12-week treatment with LA leads to improvements in reproductive hormones in serum, and significantly reduces the generation of ROS and increases the gene expression and activity of GST in seminal fluid.