Families of children with JDM have a TNFA NcoI RFLP 5.5 kb allele in linkage disequlibirum with DQA1*0501, Reed, Pachman and Ober, 1998 (in press). Others have found that specific TNFA allelic polymorphisms are associated with increased synthesis of TNFα in vitro. The purpose of this study was to determine if there were a relationship between the TNFA alleles at -308 (GG, GA,AA), the JDM disease course, the synthesis of TNFαin vitro by JDM PBMCs and serum levels of TNFα during active inflammation. 33 children with definite JDM were enrolled (12 Male, 21 Female). DNA was prepared from peripheral blood by standard methodology; the-308 fragment was amplified by PCR and analyzed using the NcoI digest. Disease activity at the time of the study was determined using a global 20 point scale. Disease course was defined as Acute mean age at study 8.3 years(active, inactive), mean disease duration 2.0 years, and Chronic. A chronic course was one that has required reinstitution of therapy, or had continued more than two years. TNFα levels (ELISA) were determined both in sera, and in the supernatant fluid of PBMCs (isolated by Ficoll-Hypaque) cultured in serum free media for 72 hours with and without PHA (viability control). There was a significant difference in genotype frequency between the Acute and Chronic groups (p=.03, Fisher's Exact Test). There was a higher frequency of the TNFA2 allele (GA,AA) in the Chronic group than published frequency(p=.005). No difference in allelic frequencies in Acute group and published frequency was seen. When the endogenous TNFα in vitro for the Acute and Chronic groups were compared, the difference was significant: p=.009. TNFα was not detectable in patients'sera. We conclude that the TNFA2 allele is associated with increased PBMC production of TNFαin vitro. We speculate that increased TNFα productionin vivo may be a significant predisposing factor for disease chronicity in children with JDM.