TERT and MUC5B polymorphisms have been associated consistently with idiopathic pulmonary fibrosis (IPF) in recent genomewide genetic studies. However, it remains unclear how both loci contribute to the susceptibility to different entities of sporadic interstitial lung disease (ILD). We sought to test the associations of the 2 polymorphisms with IPF and non-IPF ILD entities in a white population. Associations between 2 polymorphisms in TERT (rs2736100) and MUC5B (rs35705950) and IPF or non-IPF sporadic ILD were tested using 227 patients with ILD and 689 control subjects. Genotypic data were also correlated with pulmonary functions measured in patients with ILD. As a result, rs2736100 and rs35705950 were associated significantly and independently with ILD as a single phenotype (Odds ratio [OR], 1.29; 95% confidence interval [CI], 1.04–1.60; P = 2 × 10−2; and OR, 2.22; 95% CI, 1.69–2.92; P = 7 × 10−9; respectively). When considering IPF and “other ILD” (non-IPF) separately, rs35705950 had a stronger association with IPF (OR, 3.2; 95% CI, 2.21–4.63; P = 1.2 × 10−10) than with other ILD (OR, 1.72; 95% CI, 1.22–2.42; P = 1.2 × 10−3). In contrast, rs2736100 was associated with other ILD (OR, 1.43; 95% CI, 1.11–1.85; P = 6.2 × 10−3) but not with IPF (OR, 1.08; 95% CI, 0.78–1.49; P > 0.05). Rs35705950 correlated significantly with increased pulmonary function (P < 0.05). It was also associated with ILD without airflow obstruction in both the IPF and other ILD groups (P < 0.01 for both), and conferred the highest risk for IPF without airflow obstruction (OR, 4.46; 95% CI, 2.60–7.66; P = 4.5 × 10−9). Our study suggests that although both loci confer independent risks for ILD, rs35705950 may, in particular, contribute differentially to IPF and other ILD entities. Our study further highlights the genetic and phenotypic heterogeneity of ILD.