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Lyme disease is the most common vector-borne disease in the United States with an estimated 476,000 new cases per year. Delays in diagnosis and treatment are common and there is a lack of consensus on the antibiotic therapy protocols to ensure successful outcomes. Much of this discord is due to the observation that more than 50 percent of people treated with conventional antibiotic protocols, which have changed little in the last 30 years, report persistent and/or recurring symptoms within 6 months of completing treatment. Labeled as chronic Lyme or post-treatment Lyme disease, it is a syndrome that afflicts more than 2 million people in the United States and can have a devastating impact on both quality of life and socioeconomic capacity. Despite these known treatment failures, the research community has lacked the funding necessary to advance our understanding of this syndrome or to explore innovative options to improve success. In this regard, complementary and alternative therapies, which are generally not patentable and have little potential for producing large economic gain, are generally disregarded in favor of new designer drugs or old reworked protocols. Intravenous vitamin C is one such example that has research validated effectiveness for a wide range of clinical conditions ranging from infection to cancer care. Achieving serum levels much higher than could be obtained orally, high dose intravenous vitamin C has the capacity to generate a concentration of intracellular peroxide that exerts both cytotoxic and immune stimulating effects. Unfortunately, these high doses of intravenous vitamin C have never been evaluated to establish safety and tolerability in Lyme positive patients. This study’s primary aim is to examine this question with the unique additions of DMSO and calcium EDTA into the formula to enhance tissue penetration and address biofilm formation respectively, both of which are known barriers to antibiotic success. The secondary aim of the study is to determine whether subjects gain relief from Lyme-associated symptoms by tracking changes in both the PROMIS-29 and the Horowitz-Lyme-MSIDS questionnaires. The exploratory objective is to assess changes in Lyme specific labs including the standard immunoblot and the T-cell based Elispot as well as the CD57+ lymphocyte immune marker. Administered at a 75-gram dose twice weekly over 12 weeks, high dose intravenous vitamin C was shown to be both well tolerated and safe. The secondary and exploratory aims of the study provide insight into the potential efficacy of this protocol, as both subjective measures of symptom severity and objective assessment of Lyme biomarkers showed marked improvement. Ultimately, this study paves the way for future research using high dose intravenous vitamin C in Lyme patents either as a stand-alone treatment or in synergy with other therapies. It is this author’s hope that employing an integrative medical approach such as this will eventually see chronic Lyme disease as a rare rather than common occurrence.