Acute hepatic porphyria (AHP) is a group of rare, chronic, progressive, multisystem disorders with acute attacks and long-term complications. Patients with AHP can experience potentially life-threatening acute attacks and chronic manifestations (e.g., pain, fatigue, nausea between attacks), impacting daily functioning and quality of life. Treatment options for patients with AHP were limited before the approval of Givosiran. Givosiran is a newly siRNA-based treatment of AHP targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of the heme biosynthetic pathway. The ENVISION (NCT03338816), placebo-controlled phase 3 study proves the long-term efficacy and safety of Givosiran treatment in patients aged ≥12 years with AHP, leading to a reduction in porphyria attacks and days of hemin use, improving patient-rated physical and mental quality of life. This study aims to investigate the disease burden and the health-related quality of life (HRQoL) in patients with AHP in 18 months. Thus, we report data on patients with AHP enrolled in the Patient Support Programs by PHDlifescience. We used the Physical (PCS) and Mental (MCS) Composite Scores from the SF-12v1 Italian version questionnaire to assess the perception of HRQoL. PCS and MCS range from 0 to 100, with higher scores indicating better functioning. Pain intensity and its impact on patients‘ lives were assessed by the Brief Pain Inventory (BPI) questionnaire, which measures both pain interference in patients’ lives (PIS) and pain severity (PSS), with high values indicating severe interference/completely debilitating pain. Additionally, we used the Brief Fatigue Inventory (BFI) questionnaire to swiftly assess the severity of patients‘ fatigue, with higher scores indicating more pronounced fatigue. Descriptive statistics include median, 1st, and 3rd quartiles. Differences over time were assessed using Friedman’s analysis. All statistical analyses were conducted using the R environment (R Foundation for Statistical Computing, Vienna, Austria). Significance was set at p < 0.05 for all two-sided tests. The sample has a median age of 47.8 (34.7; 54.3). The clinical variables: blood pressure, heart rate, respiratory rate, oxygen saturation, body temperature, dose, and adverse events, were under control until the last follow-up. Despite no statistically significant changes, from baseline to 18 months of 7 patients with no missing values, four increased in PSI and PSS. The median PSI change was 1.8% (0.0%;34.0%) from baseline and PSS of 5.3% (-5.9%;36.5%). MCS and PCS change was 6.3% (0.1%;12.7%) and 5.3% (-5.9%;36.5%), respectively. BFI increase of 8% (-22%;13%). Although there were no statistically significant changes due to missing values and the small sample size, the clinical parameters were under control with a stable trend at 18 months. HRQoL and pain improved at the last follow-up to the baseline values.