Background HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Whey proteins are rich in cysteine as well as in GSH precursor peptides. Aim of the study In order to evaluate the effects of whey supplementation on plasma GSH levels, HIV-infected patients were treated with whey proteins for a period of six months. Methods In a double blind clinical trial, 30 patients were randomized to a daily dose of 45 g whey proteins of either Protectamin^® (Fresenius Kabi, Germany) or Immunocal^® (Immunotec, Europe) for 2 weeks. Eighteen patients (16 male, 42 ± 9.4 yr, 249 ± 99 CD4+ lymphocytes/l) continued the trial with a daily dose of 45 g of Protectamin for six months. Results Pre-therapy, total plasma GSH levels (Protectamin: 1.92 ± 0.6 μM; Immunocal: 1.99 ± 0.9 μM) were less than normal (2.64 ± 0.7 μM, p = 0.03). After two weeks of whey protein supplementation, plasma total GSH levels increased in the Protectamin group by 44 ± 56 % (2.79 ± 1.1 μM, p = 0.004), while the difference in the Immunocal group did not reach significance (+24.5 ± 59 %, 2.51 ± 1.48 μM, p = 0.43). Consequently, all patients continuing the trial were openly switched to Protectamin. After six months, total GSH plasma levels were still significantly elevated compared to baseline (day 1: 1.95 ± 0.8 μM vs. month 1: 2.18 ± 0.8 μM, p = 0.19; month 3: 2.39 ± 0.9 μM, p = 0.056; month 6: 2.47 ± 0.8 μM, p = 0.033). Body weight, T-cell counts, and other clinical parameters did not change. The most common mild side effect was intestinal disturbance; severe adverse events did not occur. Conclusion Supplementation with whey proteins persistently increased plasma glutathione levels in patients with advanced HIV-infection. The treatment was well tolerated. A larger long-term trial is clearly warranted to evaluate whether this positive influence on the glutathione metabolism translates into a more favorable course of the disease.