Purpose: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. Experimental Design: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m 2 administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B 12 , and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Results: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the “typical” Western patient receiving 500 mg/m 2 pemetrexed ± vitamin supplementation were 2.74 × 10 9 /L and 1.70 × 10 9 /L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m 2 pemetrexed with vitamin supplementation was 2.66 × 10 9 /L. Values for the 1,000 mg/m 2 dose with vitamin supplementation were 1.91 × 10 9 /L and 1.34 × 10 9 /L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. Conclusions: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.