(1) Background: Chronic inflammation and insulin resistance are associated with cardiometabolic
diseases, such as cardiovascular disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Therapeutic water-only fasting and whole-plant-food refeeding was previously shown to improve markers of cardiometabolic risk and may be an effective preventative treatment but sustained outcomes are unknown. We conducted a single-arm, open-label, observational study with a six-week post-treatment follow-up visit to assess the effects of water-only fasting and refeeding on markers of cardiometabolic risk. (2) Methods: Patients who had voluntarily elected and were approved to complete a water-only fast were recruited from a single-center residential medical facility. The primary endpoint was to describe changes to Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores between the end-of-refeed visit and the six-week follow-up visit. Additionally, we report on changes in anthropometric measures, blood lipids, high-sensitivity Creactive protein (hsCRP), and fatty liver index (FLI). Observations were made at baseline, end-of-fast (EOF), end-of-refeed (EOR), and six-week follow-up (FU). (3) Results: The study enrolled 40 overweight/ obese non-diabetic participants, of which 33 completed the full study protocol. Median
fasting, refeeding, and follow-up lengths were 14, 6, and 45 days, respectively. At the FU visit, body
weight (BW), body mass index (BMI), abdominal circumference (AC), systolic blood pressure (SBP),
diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL), hsCRP, and
FLI were significantly decreased from baseline. Triglycerides (TG) and HOMA-IR scores, which had
increased at EOR, returned to baseline values at the FU visit. (4) Conclusion: Water-only fasting
and whole-plant-food refeeding demonstrate potential for long-term improvements in markers of
cardiovascular risk including BW, BMI, AC, SBP, DBP, blood lipids, FLI, and hsCRP.