BACKGROUND Adenocarcinomas of the appendix represent a heterogeneous disease depending on the presence of mucinous histology, histologic grade, and stage. In the current study, the authors sought to explore the interplay of these factors with systemic chemotherapy in a large population data set. METHODS Patients in the National Cancer Data Base (NCDB) who were diagnosed with mucinous, nonmucinous, and signet ring cell‐type appendiceal neoplasms from 1985 through 2006 were selected. Multivariable Cox proportional hazards regression models were developed. RESULTS A total of 11,871 patients met the inclusion criteria for the current study: 50.3% had mucinous neoplasms, 40.5% had nonmucinous neoplasms, and 9.2% had signet ring cell‐type neoplasms. The 5‐year overall survival (OS) stratified by grade was similar among patients with American Joint Committee on Cancer stage I to stage III disease but not for those with stage IV disease. The median OS for patients with stage IV mucinous and nonmucinous tumors was 6.4 years and 2.3 years, respectively, for those with well differentiated histology (P<.0001) and was 1.5 years and 0.8 years, respectively, for those with poorly differentiated histology (P<.0001). In multivariable modeling for stage I to III disease, adjuvant chemotherapy improved OS for both mucinous and nonmucinous histologies, with hazard ratios (HRs) of 0.78 (95% confidence interval 95% CI, 0.68‐0.89 P = .0002) and 0.83 (95% CI, 0.74‐0.94 P = .002), respectively. For patients with stage IV disease, systemic chemotherapy significantly improved OS for those with nonmucinous (HR, 0.72; 95% CI, 0.64‐0.82 P<.0001) but not mucinous (HR, 0.95; 95% CI, 0.86‐1.04 P = .2) histologies, although this was grade‐dependent. The median OS for chemotherapy versus no chemotherapy was 6.4 years versus 6.5 years (P value not significant) for patients with mucinous, well‐differentiated tumors and 1.6 years versus 1.0 years (P = .0007) for patients with mucinous, poorly differentiated tumors. CONCLUSIONS Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for patients with stage IV disease, the benefit of systemic chemotherapy varied by tumor histology and grade, with patients with well‐differentiated, mucinous, appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy. Cancer 2016;122:213–221. © 2015 American Cancer Society. Adjuvant chemotherapy results in an improvement in overall survival for patients with resected mucinous and nonmucinous appendiceal adenocarcinomas. However, for those with American Joint Committee on Cancer stage IV disease, the benefit of systemic chemotherapy appears to vary by histology and grade, with patients with well‐differentiated, mucinous appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy.