Background: Lymphopenia is associated with adverse prognosis in chronic disease states that are related to immune dysregulation. We aimed to determine the association between lymphopenia and mortality in patients presenting to coronary angiography and investigate whether elevated red blood cell distribution width (RDW), an established cardiovascular prognostic marker, further refines risk stratification. Methods: Retrospective analysis of patients undergoing coronary angiography for evaluation or treatment of coronary artery disease between 2003 and 2018. Mortality risk associated with relative (1000–1500/μL) or severe ( < 1000/μL) lymphopenia was analyzed using adjusted Cox proportional hazards regression models. Results: Overall, 15,179 patients aged 65 ± 12 years underwent coronary angiography. During a median follow-up of 8 years, 4253 patients died. Compared to normal lymphocyte count, the adjusted hazard ratio (HR) for mortality was 1.31 (95% confidence interval [CI] 1.21–1.41) and 1.97 (95% CI 1.75–2.22) for relative and severe lymphopenia, respectively. The increase in mortality associated with severe lymphopenia was significant in patients presenting in the non-acute setting (HR 2.18, 95% CI 1.74–2.73), ST-segment elevation myocardial infarction (STEMI) (HR 1.59, 95% CI 1.15–2.21), or unstable angina/non-STEMI (HR 2.00, 95% CI 1.70–2.34); p-value for interaction 0.626. The association of lymphopenia with mortality remained significant after additional adjustment to RDW. High RDW ( > 14.5%) was associated with reduced survival, and it improved the predictive accuracy of lymphocytes count with an increase in Harrell’s Concordance statistic from 0.634 (SE = 0.005) to 0.672 (SE = 0.005), p < 0.001. Conclusions: lymphopenia is associated with increased risk of mortality during long-term follow-up in patients undergoing coronary angiography, regardless of the coronary presentation. High RDW may enhance the predictive ability of lymphopenia.