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Purpose/objective(s): Collagen vascular disease (CVD) is considered a relative contra-indication to radiotherapy. We sought to determine rates of acute and late radiotherapy-associated toxicity in patients with CVD compared to matched controls.Materials/methods: A systematic review was performed following PRISMA guidelines. PubMed was searched for articles from inception to February 2021. Search terms included collagen vascular disease and subtypes; radiotherapy; and cancer. Eligible studies included radiotherapy-associated toxicity rates for at least 10 patients with CVD and their matched controls. Data abstracted included number of patients with CVD; number of controls; median follow-up; treatment period; anatomic sites treated; types of CVD; acute toxicity and late toxicity. Primary endpoints were acute and late grade 3 or higher (3+) toxicity. Random effects meta-analyses of acute and late grade 3+ toxicity were performed using Comprehensive Meta-analysis software for patients with any CVD and their matched controls; patients with scleroderma and their matched controls; and patients with Lupus and their matched controls.Results: The search strategy identified 3573 studies. 17 articles were selected for full-text review and 7 were included for analysis for the primary endpoints. Patients received radiotherapy between 1964 and 2016. 353 patients with CVD were matched to 617 controls, including 19 patients with scleroderma matched to 40 controls and 48 patients with Lupus matched to 82 controls. The most common sites treated were head and neck (31%), breast (29%), and pelvis (11%). Criteria for propensity score included: age, sex, cancer diagnosis, radiotherapy technique, radiotherapy dose, year of radiotherapy and anatomical site of treatment. Patients with CVD had an increased rate of acute grade 3+ toxicity compared to controls (15% vs 9%, P < 0.01, OR = 2.0) and a trend toward an increased rate of late grade 3+ toxicity (11% vs 6%, P = 0.05, OR = 1.7). Patients with scleroderma had an especially high acute grade 3+ toxicity rate compared to controls (25% vs 6%, P = 0.03, OR = 4.1). There was no significant difference in late grade 3+ toxicity between scleroderma patients and their matched controls, and no significant difference in acute or late grade 3+ toxicity between Lupus patients and their matched controls. 5 patients with CVD and no matched controls had treatment-related death.Conclusion: Patients with CVD have a higher rate of acute grade 3+ radiotherapy toxicity compared to matched controls. [ABSTRACT FROM AUTHOR]