Objective. Agmatine, decarboxylated arginine, was shown in preclinical studies to exert efficacious neuroprotection by interacting with multiple molecular targets. This study was designed to ascertain safety and efficacy of dietary agmatine sulfate in herniated lumbar disc-associated radiculopathy. Study Design. First, an open-label dose escalation study was performed to assess the safety and side-effects of agmatine sulfate. In the follow-up study, participants diagnosed with herniated lumbar disc-associated radiculopathy were randomly assigned to receive either placebo or agmatine sulfate in a double-blind fashion. Methods. Participants in the first study were recruited consecutively into four cohorts who took the following escalating regimens: 1.335 g/day agmatine sulfate for 10 days, 2.670 g/day for 10 days, 3.560 g/day for 10 days, and 3.560 g/day for 21 days. Participants in the follow-up study were assigned to receive either placebo or agmatine sulfate, 2.670 g/day for 14 days. Primary outcome measures were pain using the visual analog scale, the McGill pain questionnaire and the Oswestry disability index, sensorimotor deficits, and health-related quality of life using the 36-item short form (SF-36) questionnaire. Secondary outcomes included other treatment options, and safety and tolerability assessment. Results. Safety parameters were within normal values in all participants of the first study. Three participants in the highest dose cohort had mild-to-moderate diarrhea and mild nausea during treatment, which disappeared upon treatment cessation. No other events were observed. In the follow-up study, 51 participants were randomly enrolled in the agmatine group and 48 in the placebo. Continuous improvement of symptoms occurred in both groups, but was more pronounced in the agmatine (analyzed n = 31) as compared with the placebo group (n = 30). Expressed as percent of baseline values, significantly enhanced improvement in average pain measures and in quality of life scores occurred after treatment in the agmatine group (26.7% and 70.8%, respectively) as compared with placebo (6.0% [P </= 0.05] and 20.0% [P </= 0.05], respectively). No treatment-related adverse events were noted. Conclusions. Dietary agmatine sulfate is safe and efficacious treatment for alleviating pain and improving quality of life in lumbar disc-associated radiculopathy. Study Registration. ClinicalTrials.gov Protocol Registration System Identifier: NCT00405041.