Aim: To investigate associations between clinical factors and the development of autism spectrum disorder (ASD) in children with tuberous sclerosis complex (TSC), specifically seizures, electroencephalogram abnormalities, tubers and other neurostructural abnormalities, and genetic factors. Method: MEDLINE, Embase, PubMed, the Cochrane Library, and Web of Science were searched until January 2019. Studies that considered the predefined factors for development of ASD in children with TSC were included, following PRISMA-P guidelines. Two authors independently reviewed titles, abstracts, and full texts, extracted data, and assessed risk of bias. Results: Forty-two studies with 3542 children with TSC were included. ASD was associated with a history of seizures (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.77–8.14), infantile spasms compared with other seizure types (OR 3.04, 95% CI 2.17–4.27), onset of any seizure type during infancy (OR 2.65, 95% CI 1.08–6.54), and male sex (OR 1.62, 95% CI 1.23–2.14). There was no association with tuber number, tuber location, or genotype. Interpretation: While a causal link between seizures and ASD in children with TSC cannot be inferred, a strong association between seizures and ASD in children with TSC, particularly with seizure onset during infancy and specifically infantile spasms, is present. Children with TSC and infant-onset seizures should be monitored for emerging features of ASD.