OBJECTIVES: To determine whether chemotherapy response and diagnostic delay affect overall survival (OS) of classic inflammatory breast cancer (IBC) cases receiving chemotherapy as initial treatment and to determine whether OS differs between classic and "atypical" IBC cases. METHODS: This is a prospective cohort study of 155 patients enrolled in the IBC Registry. "Classic" IBC cases met AJCC or SEER case definitions. "Atypical" IBC cases exhibited classic features but involved <1/2 breast without documented dermal lymphatic invasion. Variables included OS (years from initial chemotherapy treatment until death or last contact), chemotherapy response (complete, partial, or none), diagnostic delay (days from first medical contact for signs/symptoms of abnormal breast to definitive pathologic IBC diagnosis), age at diagnosis (y), and triple-negative status (yes or no). OS curves stratified by individual predictors were estimated and compared using Kaplan-Meier methods and log-rank tests. Associations between OS and predictors were examined collectively using Cox proportional hazards regression. RESULTS: Classic IBC cases with complete, partial, or no response had respective median (95% confidence interval [CI]) OS times of 10.30 (6.78, +), 6.27 (4.42, +), and 2.86 (1.11, 11.42) years (P=0.0072). Chemotherapy response was significantly associated with OS after controlling for covariates (P=0.003). Women not responding to chemotherapy had a significantly higher hazard of death compared with women with complete (hazard ratio [HR]=5.76; 95% CI, 2.09-15.84) or partial (HR=3.40; 95% CI, 1.27-9.10) response. Diagnostic delay was not significantly associated with OS (HR=1.003; 95% CI, 0.999-1.007). OS did not differ significantly between classic and "atypical" IBC cases (P=0.60). CONCLUSIONS: Response to standard IBC chemotherapy is a dominant prognostic factor in determining patient outcomes. In our study, with limited statistical power, delay in diagnosis defined as >60 days from the time of first physician contact did not seem to affect patient outcomes. Data support similarities between classic and "atypical" IBC.