Background <p>Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Lymphocytes play an important role in sepsis, but little is known about the comparisons of different lymphopenia and non-lymphopenia patients with septic shock. The aim of this study is to compare the clinical characteristics of patients with septic shock among pre-existing lymphopenia group, sepsis-induced lymphopenia group, and non-lymphopenia group, and to identify the relationship of different lymphopenia with outcomes.</p> Methods <p>This retrospective study included 354 septic-shock patients with baseline lymphocyte available during 2013 and 2023, which were divided into pre-existing lymphopenia group, sepsis-induced lymphopenia group, and non-lymphopenia group. We compared the clinical characteristics and identified the relationship of different lymphopenia with 30-day mortality by univariate analysis and multivariable logistic regression analysis.</p> Results <p>Among 354 patients with septic shock with baseline lymphocyte available, the pre-existing lymphopenia group (<i>n</i> = 159) exhibited the highest 30-day mortality (50.9%), while the mortality in sepsis-induced lymphopenia patients (<i>n</i> = 143) and non-lymphopenia groups (<i>n</i> = 52) was 37.1% and 44.2%, respectively (<i>p</i> = 0.069). Multivariable analysis showed that pre-existing lymphopenia was an independent risk factor for 30-day mortality (OR 3.67, 95% CI 1.61–8.79), while lymphopenia at ICU admission was not (OR 0.95, 95% CI 0.28–3.37).</p> Conclusion <p>Pre-existing lymphopenia was an independent risk factor for 30-day mortality in patients with septic shock, while sepsis-induced lymphopenia at ICU admission was not. These results suggest that historical lymphocyte count level should be incorporated into risk stratification paradigms for septic shock patients.</p>