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Background Adenocarcinomas of the appendix represent a heterogeneous disease depending upon the presence of mucinous histology, histologic grade, and stage. We sought to explore the interplay of these factors with systemic chemotherapy in a large population dataset. Methods Patients in the National Cancer Data Base (NCDB) with mucinous, non-mucinous and signet-ring cell type appendiceal neoplasms from 1985-2006 were selected. Multivariable Cox proportional hazards regression models were developed. Results 11,871 patients met our inclusion criteria: 50.3% mucinous, 40.5% non-mucinous and 9.2% signet-ring cell. 5-year overall survival (OS) stratified by grade was similar across stage I-III disease but not for stage IV disease. Median OS for stage IV mucinous and non-mucinous histology was 6.4 and 2.3 years for well differentiated (p<0.0001) and 1.5 and 0.8 years for poorly differentiated (p<0.0001), respectively. In multivariable modeling for stage I-III disease, adjuvant chemotherapy improved OS for both mucinous and non-mucinous histologies: HR of 0.78 (0.68-0.89; p=0.0002) and 0.83 (0.74-0.94;p=0.002) respectively. For stage IV disease systemic chemotherapy was significant for non-mucinous 0.72 (0.64-0.82; p<0.0001) but not mucinous 0.95 (0.86-1.04; p=0.2) histologies, though this was grade dependent. Median OS for chemotherapy vs. no chemotherapy was 6.4 versus 6.5 years. (p=not significant) for mucinous well differentiated and 1.6 versus 1.0 years. (p=0.0007) for mucinous poorly differentiated. Conclusions Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for stage IV disease the benefit of systemic chemotherapy varied by histology and grade, with well differentiated mucinous appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy.