402 Background: Our previous observation showed germ cell tumor (GCT) patients who finished at first-, second- or third-line chemotherapy obtained good overall survival. On the other hand, patients with 4th line-or-after chemotherapy showed much poorer outcome. The aim of this study was to investigate the prognostic factor for overall survival in the patients with 4th-line-or-after chemotherapy. Methods: Between August 1998 and December 2013, seventy-four GCT patients had 4th line-or-after chemotherapy at our institution. These patients were defined as ‘difficult-to-treat’ GCT patients in this study. We retrospectively assessed clinical and therapeutic parameters. Median age was 33 y.o.(range;19-55). Nonseminoma was found in 86.5%. Good, intermediate and poor prognosis by IGCCC was 23, 17 and 26 cases, respectively. With regard to IGCCC at salvage, very low, low, intermediate, high and very high was 2, 7, 10, 18 and 6 cases, respectively. Results: Fiver-year overall survival was 55.6%. Choice of 2nd line or 3rd line chemotherapy did not influence overall survival, for example, VeIP (vinblastine, ifosfamide, cisplatin) or VIP (etoposide, ifosfamide, cisplatin) versus other chemotherapy as 2nd line therapy (5-y OS; 55.2% and 56.3%, log-rank, p=0.78). The identical result was observed in paclitaxel-containing therapy such as TIP versus other chemotherapy (paclitaxel, ifosfamide, cisplatin) (5-y OS; 52.8% and 57.1%, log-rank, p=0.90). In the choice of 4th line chemotherapy, gemcitabine-containing regimen was not superior to other chemotherapy (5-y OS; 57.0% and 55.3%, log-rank, p=0.98). Statistical significant parameters were primary site, IGCCC at salvage, required chemotherapy line and serum tumor marker (STM) normalization by univariate analysis. Multivariate analysis showed independent prognostic factor for overall survival was normalization of serum tumor marker during chemotherapy (Hazard Ratio;0.12, 95% Confidence Interval;0.02-0.62, p=0.01). Conclusions: STM normalization is thought to be mandatory for overall survival in the management of ‘difficult-to-treat’ advanced GCT patients.