More than 80% of patients with systemic sclerosis (SSc) develop lung involvement, most commonly interstitial pneumonia (IP). We recently identified a common variant in the promoter region of MUC5B (rs35705950) that has a significant effect on the risk of developing both familial and sporadic forms of IP. We hypothesized that this MUC5B promoter polymorphism is also associated with IP in subjects with SSc.We examined the minor allele frequency of the MUC5B polymorphism among 231 subjects with SSc, 109 with IP, and 122 without IP. IP diagnosis was confirmed by HRCT imaging and defined as the presence of reticular infiltrates and/or honeycomb cysts. FVC and diffusing capacity of the lung for carbon monoxide (Dlco) were also assessed.We found no association between IP and the MUC5B polymorphism among subjects with SSc (OR = 1.1, P = .80). The frequencies of the MUC5B polymorphism among subjects with SSc with IP (10.6%) and without IP (9.4%) were similar to the frequency observed in a population of unaffected control subjects (9.0%). In secondary analyses, we found the MUC5B polymorphism was not significantly associated with either FVC (P = .42) or Dlco (P = .06). No association with SSc-associated IP was found even when we used a more conservative definition of IP (FVC ≤ 70% and evidence of reticulations or honeycombing vs SSc FVC > 70% and no evidence of reticulation or honeycombing).Although SSc-associated IP is clinically, radiologically, and histologically similar to other forms of IP, it appears to have distinct genetic risk factors. This study highlights the genetic and phenotypic heterogeneity of IP in general.