Objective K. K. and S.-K. C. are co-first authors, and C. K. and S.-C. B. are co-senior authors. Two transcription factors in the type I interferon pathway, IRF5 and STAT4, have been genetically associated with susceptibility to both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to determine whether these two genes interact with each other to affect the disease susceptibilities. Methods The genetic interactions between IRF5 and STAT4 polymorphisms in SLE and RA susceptibility were examined using the epistasis options in PLINK software. This study analyzes the genetic data from 2558 unrelated Korean participants including 589 SLE patients, 987 RA patients, and 982 controls. Results All 12 polymorphisms were individually associated with SLE susceptibility ( p = 2.49 × 10−8 to 0.00360). Among the three SLE-associated polymorphisms of IRF5, rs77571059, alternatively called CGGGG(3–4) indel, exhibited the lowest p value (4.60 × 10−5) and accounted for the observed associations of the other two single-nucleotide polymorphisms (SNPs). Among the nine SLE-associated SNPs of STAT4, rs16833215 exhibited the lowest p value (2.49 × 10−8) and accounted for all the other associations. These two polymorphisms, rs77571059 of IRF5 and rs16833215 of STAT4, interacted with each other for SLE susceptibility in a redundant manner (ORinteraction = 0.77, Pepistasis = 0.040). Furthermore, these two polymorphisms, which had been individually associated with RA susceptibility, also interacted for RA susceptibility in the same manner (ORinteraction = 0.75, Pepistasis = 0.014). Conclusions A redundant interaction between IRF5 and STAT4 polymorphisms was found in susceptibility to the type I interferon pathway-associated rheumatic autoimmune diseases, SLE and RA, calling for further studies on confirmation of these findings.