Introduction: This study evaluated the effects of pretreatments with melatonin (MT), and Alpha Lipoic acid (ALA) on lopinavir/ritonavir (LPV/r) -induced serum levels of creatinine (Cr), urea (U), uric acid (Ua) and kidney levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in male albino rats. Effects of treatments with MT and ALA were also evaluated on baseline levels of the above parameters. Materials and Methods: Adult male albino rats orally received MT (10mg/kg), ALA (10mg/kg) and LPV/r (22.9/5.71, 45.6/11.4 and 91.4/22.9mg/kg) for 60 days. At the end of drug treatment animals were sacrificed, serum was extracted and evaluated for Cr, U, and Ua. Kidney was harvested and evaluated for MDA, SOD, CAT and GSH. Results: Treatment with MT and ALA significantly (p<0.05) decreased baseline serum levels of Cr, U, Ua and kidney MDA level while kidney levels of SOD, CAT and GSH were decreased when compared to the control. On the contrary, treatment with LPV/r significantly (p<0.05) and dose -dependently increased serum Cr, U, Ua levels and kidney MDA level while kidney levels of SOD, CAT and GSH were decreased when compared to the control. But pretreatments with MT and ALA mitigated LPV/r induced changes in all evaluated parameters. Pronounced mitigation was observed with pretreatment using a combination of MT and ALA. Conclusion: Observations in this study may be due to the oxidant effect of LPV/r and the antioxidant effects of MT and ALA. This study, therefore recommends MT and ALA as treatment or prevention for LPV/r induced renal toxicity.