Background <p>Progesterone receptors (PRs) play a role in the regulation of cell proliferation and are expressed in non-small cell lung cancer (NSCLC) tissue. Therefore, they represent a potential target for novel antitumor therapies. A survival analysis of NSCLC patients based on PR expression in tumor tissue may help assess the feasibility of using PR modulators in the treatment of this disease.</p> Aim <p>This study aims to evaluate the prognostic significance of PR expression in NSCLC to determine the potential utility of PR modulators as a therapeutic strategy.</p> Methods <p>PR expression was assessed in 130 surgically resected NSCLC samples using immunofluorescence analysis combined with flow cytometry. Primary antibodies against PR (NBP2-4638, Novus Biologicals, USA) and secondary antibodies conjugated with DyLight650 (ab98729, Abcam, UK) were used. The percentage of PR-expressing cells was quantified using FlowJo software. Statistical analyses were conducted in GraphPad Prism and RStudio using the “survival” package. The prognostic impact of PR expression in NSCLC tissue was evaluated in the overall patient cohort and after excluding censored events (<i>n</i> = 56) to minimize the influence of confounding factors on survival analysis.</p> Results <p>After excluding censored events and stratifying patients based on the median PR expression level (57%), survival analysis revealed that high PR expression in NSCLC tissue is associated with a poorer prognosis (<i>p</i> = 0.05). Patients with high PR expression (≥ 57%) had a median survival of 12.8&#xa0;months, whereas those with low PR expression (&lt; 57%) had a median survival of 25.8&#xa0;months (HR = 1.7).</p> Conclusions <p>Elevated PR expression in NSCLC tumors is associated with reduced patient survival. These findings suggest that PR modulators may have potential therapeutic value for NSCLC patients with PR-positive tumors.</p>