Background and Significance: The major clinical issues that impact myeloproliferative neoplasm (MPN) patients are thromboses, debilitating symptoms such as itching and fatigue, and progression to acute leukemia. There are no available therapies that address all three of these issues. We have found that N-acetylcysteine (N-AC), an anti-oxidant with an established safety profile, protects animal MPN models from thrombosis and extends survival. Moreover, N-AC is known to reduce inflammation and protect cells from DNA damage, properties which are likely to be beneficial for reduction in symptoms and prevention of leukemia, respectively. We are performing a Phase I/II optimal biological dose (OBD) finding study. Our goals with this initial dose finding study are 1) to identify a dose which has a signal of efficacy (based on reduction in MPN symptom burden) without excessive toxicity and 2) to explore biological correlates of oxidative stress, inflammation, and thrombosis. Study Design and Methods: We have obtained an IND, IRB approval and opened for recruitment in January 2022 (NCT05123365). Nine patients have been enrolled. This is a single center study performed at University of California, Irvine. We are recruiting patients with all types of classic Ph-neg myeloproliferative neoplasms (ET, PV, MF). Patients must be symptomatic with an MPN symptom score (MPN-TSS) of ≥ 10. Patients on interferon-alpha or JAK inhibitors are excluded, however all other MPN directed therapies are allowed. We are using a Simple Toxicity and Efficacy Interval (STEIN) design for phase I/II trials which identifies the OBD based on both safety and efficacy. In contrast, the conventional 3+3, continuous reassessment method (model based Bayesian method) or Bayesian optimal interval designs for phase I dose finding study determine the maximum tolerable dose (MTD) solely on toxicity. The STEIN design is simple, robust and does not have strict assumptions. We will accrue patients in up to 9 cohorts of size 3 for a total of up to 27 patients. Three dose levels will be evaluated (600mg BID, 1200mg BID, 1800mg BID). Patients receive N-AC for a total of 8 weeks. For efficacy, the MPN symptom score (MPN-TSS) is assessed daily from the time of enrollment for 7 days before starting treatment to quantify the mean baseline symptom score and daily for 7 days during the last week of treatment (days 50-56) to assess the mean final symptom score. The desired target efficacy outcome is achievement of more than 30% reduction of MPN-TSS from baseline. Patients are monitored for toxicity with adverse event queries and labs including complete blood counts (CBC) and comprehensive metabolic panel (CMP) at weeks 1, 3, 6, 8, and 12 (week 12 is 30 day post-treatment follow-up). Dose-limiting toxicity (DLT) is defined as hematologic and non-hematologic toxicity, grade 3 or more according to The Common Terminology Criteria for Adverse Events (CTCAE Version 5), reported from the day of starting N-AC through the follow up period. N-AC possesses anti-oxidant, anti-inflammatory, and anti-thrombotic properties. Quantifying biologic measures of these features of N-AC at each dose level will help identify the specific mechanism(s) by which N-AC may be inducing benefit in MPN patients. At week 1 (immediately before initiating treatment) and Week 8 (last week of treatment) biological samples will be used for biological correlates. Plasma will be frozen within 2 hours of draw for metabolomics, multiplex cytokine array, and assessment of neutrophil extracellular trap (NET) formation by citrullinated histone H3 (H3Cit). We will also collect a stool sample at week 1 and week 8 to explore any changes in the gut microbiome.