In patients with non-small cell lung cancer (NSCLC), tumor expression of P21-Ras, HER2, P53, and Bcl-2 has been reported as independent predictors of prognosis. However, the prognostic information carried by these proteins has usually been determined separately, and their potential interaction has not been taken into account. We conducted immunostaining for P21-Ras, HER2, P53 and Bcl-2 on 238 cases of NSCLC in a Korean population with 203 squamous cell carcinomas, and 35 adenocarcinomas. P21-Ras, HER2, P53 or Bcl-2 was expressed at high levels in 54.6, 42.0, 18.1 and 71.8% of the NSCLC studied, respectively. A total of 59 tumors (24.8%) expressed only one protein, while 70 (29.4%) expressed two, 59 (24.8) expressed three, and 17 tumors (7.1%) expressed all four proteins. Univariate analysis testing the association of marker expression with survival found Bcl-2 expression to be significantly associated with a poor prognosis, as well as the co-expression of Bcl-2 + HER2, Bcl-2 + HER2 + P53, and Bcl-2 + HER2 + P53 + P21-ras with an increasing hazard ratio. By multivariate analysis controlling for age, tumor stage and tumor type, only the combination of Bcl-2 + HER2 expression was an independent marker of poor prognosis (hazard ratio = 1.91, P = 0.003). Thus, a prospective analysis of the co-expression of Bcl-2 + HER2 in NSCLC patients may identify patients with a poor prognosis who may benefit from more aggressive therapy.