Although women have an increased susceptibility to lung cancer, they also have a favorable clinical outcome. This may in part be due to female specific genetic and hormonal factors. In the present study, expression of ER-beta was investigated by immunohistochemistry using tissue samples from two cohorts: non-small cell lung cancer (NSCLC) diagnosed in 1999 in Manitoba and advanced NSCLC patients from the NCIC-CTG BR.18 trial. In the Manitoba cohort assessable tissue samples available in 79 patients (32 females and 47 males) and the majority (75%) had early stage disease. Fifty-one percent of patients expressed high levels of ER-beta (defined by ≥60, the median immunohistochemistry score) and its expression was comparable in males and females. The 3-year overall survival of the group was 53% and males had significantly worse survival compared to females (HR=2.37, 95%CI 1.15–4.91, P=0.02). Higher ER-beta 1 expression was associated with better survival in both univariate (HR=0.41, 95%CI 0.21–0.80, P=0.009) and in multivariate (HR=0.37, 95%CI 0.18–0.77, P=0.008) analysis. In the NCIC-CTG cohort that were more often later stage, assessable tissue samples from 48 cases were available however higher ER beta 1 expression correlated with poorer survival (HR= 1.94, 95%CI 1.01–3.75 P=0.047). These results suggest a differential impact of ER-beta 1 expression on clinical outcome by disease stage, that needs to be explored further and may explain contradictory observations reported in the literature.