Objective <p>This study aimed to investigate the potential of lymphocyte-to-C-reactive protein ratio (LCR) upon admission to predict therapeutic responsiveness to mesalazine in adult patients with mild-to-moderate active ulcerative colitis (UC).</p> Methods <p>This single-center cohort study retrospectively recruited adult patients with mild-to-moderate active UC who received mesalazine monotherapy as first-line treatment and underwent the first lower digestive endoscopy within 7 days after admission. Multiple demographic characteristics and clinical indicators were extracted, collated, and calculated from the medical records. Based on their therapeutic responsiveness to mesalazine, the enrolled patients were classified into the therapeutic responsiveness to mesalazine group and the therapeutic non-responsiveness to mesalazine group, respectively. All the aforementioned data were compared between different groups.</p> Results <p>A total of 244 adult patients with mild-to-moderate active UC were recruited and subsequently stratified into the therapeutic responsiveness to mesalazine group (<i>n</i> = 165) and the therapeutic non-responsiveness to mesalazine group (<i>n</i> = 79). The overall therapeutic responsiveness to mesalazine in adult patients with mild-to-moderate active UC was 67.62%. LCR upon admission exhibited a significant positive correlation with disease duration and remarkable negative correlations with disease severity as well as the first ulcerative colitis endoscopic index of severity (UCEIS) and Mayo endoscopic score (MES) within 7 days after admission. Disease duration, neutrophil percentage (NEUT%), and LCR upon admission were determined as protective factors for therapeutic responsiveness to mesalazine, whereas disease severity, the first UCEIS within 7 days after admission, and length of hospital stay were identified as risk factors. The areas under the receiver operating characteristic (ROC) curves (AUCs) of disease duration, disease severity, NEUT%, LCR, UCEIS, length of hospital stay, and combination of disease duration, disease severity, NEUT%, LCR, UCEIS, and length of hospital stay were 0.614, 0.818, 0.637, 0.907, 0.800, 0.738, and 0.938, respectively.</p> Conclusion <p>LCR upon admission holds significant potential to predict therapeutic responsiveness to mesalazine in adult patients with mild-to-moderate active UC.</p>