Background Methotrexate (MTX) and leflunomide are commonly used among patients with psoriasis and rheumatoid arthritis (RA) and are implicated in hepatotoxicity. We aimed to determine the prevalence of significant liver fibrosis and its risk factors in patients with psoriasis and RA. We also explored the role of novel serum biomarkers to identify significant liver fibrosis in these patients. Methods A total of 318 patients attending dermatology-rheumatology clinics in Queen Mary Hospital, with clinical diagnosis of psoriasis or RA were recruited from August 2020 to July 2022. Liver fibrosis was assessed by transient elastography (TE) and serum biomarkers for liver fibrosis, namely autotaxin and matrix metalloproteinase (MMP), were measured. Risk factors associated with significant liver fibrosis (defined as liver stiffness [LS] ≥7.1kPa) were analyzed by multivariate regression models. Results A total of 67 (21.1%) patients with psoriasis or RA had significant liver fibrosis. Body mass index (OR 1.14, 95%CI 1.04-1.24), diabetes mellitus (OR 1.93, 95%CI 1.25-2.98) and PASI (OR 1.13, 95%CI 1.05-1.27), but not cumulative dosage (CD) of MTX or leflunomide, were independently associated with significant liver fibrosis (all p<0.01). Serum MMP 3,8,9 and autotaxin levels were significantly higher among patients with advanced liver fibrosis (LS≥14 kPa). Serum autotaxin showed modest correlation with LS (r=0.31, p=0.026) and CD of MTX (r=0.30, p<0.001). Conclusion Significant liver fibrosis in patients with psoriasis and RA is related to the underlying metabolic risk factors and independent of MTX and leflunomide CD. Minimising hepatic risks by tight control of metabolic risk factors should be considered.