The effect of direct-acting antiviral agents (DAAs) on short-term platelet improvement in chronic hepatitis C (CHC) patients with thrombocytopenia is unclear.From December 2015 to March 2018, a total of 249 CHC patients receiving DAA treatment with baseline thrombocytopenia (platelet count <150 × 10 /μL) at Dalin Tzu Chi Hospital were enrolled in this retrospective study. Blood examinations were conducted at baseline (BL), week 4 (W4) after DAA initiation, end of treatment (EOT), and 12 weeks after EOT (P12).Hepatitis C virus (HCV) genotyping revealed that 184 patients (73.9%) carried HCV genotype 1. Of the patients in the cohort, 87 (34.9%) were interferon (IFN)-experienced, and 213 (85.5%) had advanced fibrosis. All but 1 patient achieved SVR12 (sustained virologic response (SVR) rate, 99.6%; 248/249). The platelet count recovered significantly in 104 patients (41.7%; 104/249). The mean baseline platelet count was 102 × 10/μL before DAA, increasing to 116 × 10/μL, 114 × 10/μL, and 113 × 10/μL at W4, EOT, and P12, respectively. Comparison of the mean platelet count at baseline with that at W4, EOT, and P 12 showed statistically significant increases at all time points (W4 vs BL, P < .001; EOT vs BL, P < .001; P12 vs BL, P < .001). Multivariate analyses revealed moderate or severe fatty liver (P = .024) and lower baseline platelet count (P = .005) was significantly associated with platelet count improvement.In conclusion, thrombocytopenia associated with CHC rapidly improves with the administration of DAA. Moderate or severe fatty liver and lower baseline platelet count predict significant improvement of platelet count.