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Background Obsessive-compulsive spectrum disorders (OCSDs) are more frequent in patients with active or prior rheumatic fever (RF), suggesting that OCSD and RF may share underlying etiologic mechanisms. Our objective was to estimate the frequency of OCSD in first-degree relatives (FDRs) of RF patients and controls to determine whether there is a familial relationship between OCSD and RF. Methods This is a case-control family study. Of the 98 probands included in this study, 31 had RF without Sydenham’s chorea (SC) and had 131 relatives, 28 had RF with SC and had 120 relatives, and 39 were controls without RF. All probands, 87.9% of the RF FDRs and 93.7% of the control FDRs were assessed directly with structured psychiatric interviews and best-estimate diagnoses were assigned. Odds ratios of morbid risks were estimated using logistic regression by the generalized estimating equations (GEE) method and compared between groups. Results The rate of OCSDs was significantly higher among FDRs of RF probands than among FDRs of controls ( n =37; 14.7% vs. n =10; 7.3%, i=.0279). A diagnosis of OCSDs in an RF proband was associated with a higher rate of OCSDs among FDRs when compared to control FDRs ( p-GEE =.02). There was a trend for a higher rate of OCSDs among FDRs of RF probands presenting no OCSD, although the difference was not significant ( p-GEE =.09). Conclusion The results are consistent with the hypothesis that a familial relationship exists between OCSD and RF, since an OCSD in the RF proband was found to increase the risk of OCSDs among FDRs. Additional neuroimmunological and genetic studies involving larger samples are needed to further elucidate this apparent familial relationship between RF and OCSD.