Background:Inclisiran, a novel small interfering RNA (siRNA) therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), has demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C). While generally well-tolerated, emerging evidence has highlighted safety concerns, particularly joint-related adverse events (AEs), such as arthralgia. atorvastatin, a commonly prescribed lipid-lowering agent, is also associated with joint-related AEs, leading to concerns about the safety of concomitant use. This study utilized the FDA Adverse Event Reporting System (FAERS) to evaluate inclisiran’s safety profile, with a specific focus on its monotherapy and combination therapy with atorvastatin. Methods :A retrospective pharmacovigilance study was conducted using FAERS data from 2004 to 2024.Advanced signal detection algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Bayesian Confidence Propagation Neural Network (BCPNN), were employed to detect significant AEs. Data cleaning and standardization were performed using MedDRA terminology. Analyses included signal detection by System Organ Classes (SOCs), Preferred Terms (PTs), drug-drug interaction (DDI) analysis to detect signal. Result:Among 4269 AE reports related to inclisiran, 48.3% were from females, and 31.4% involved individuals ≥65 years. The United States contributed 84.4% of reports, reflecting higher pharmacovigilance reporting in this region.The SOC signal detection indicates that the most frequently reported SOCs included ”general disorders and administration site conditions” (23.78%) and ”musculoskeletal and connective tissue disorders” (16.88%). The PT signal detection indicates Arthralgia was the most reported PT (512 reports; ROR: 5.84, 95% CI: 5.35–6.39), followed by injection site pain and myalgia. The interaction between inclisiran and atorvastatin indicates that Combination therapy was associated with significant signals for musculoskeletal AEs, with synergistic effects noted in joint-related conditions. Conclusion：This comprehensive pharmacovigilance analysis highlights the safety profile of inclisiran, identifying musculoskeletal and injection site-related AEs as primary concerns. The findings emphasize the need for early monitoring during Inclisiran therapy, particularly in at-risk populations such as females, older adults, and those on combination therapy with atorvastatin. Enhanced pharmacovigilance frameworks and real-world evidence are essential to mitigate AE risks and inform clinical practice.