BACKGROUND Results of some studies suggest that prenatal antidepressant exposure increases the risk of autism spectrum disorder (ASD) in offspring, while other studies suggest that depression independently increases the risk of having a child with ASD. Thus, confounding by indication is a concern. OBJECTIVE The aim of this study was to estimate the risk of ASD in offspring of women who were exposed to antidepressants and/or had depression during pregnancy compared to unexposed women. METHODS We conducted a cohort study with nested sibling case-control analysis. Using the UK Clinical Practice Research Datalink (CPRD), we identified mother- baby pairs where the mother had ≥12 months of history before the delivery date and the child had ≥3 years of follow-up. Exposures during pregnancy were classified as 1) depression treated with antidepressants, 2) untreated depression, 3) other indications for antidepressant use, and 4) 4:1 match of unexposed women with no history of depression or antidepressant use. We calculated the prevalence of ASD and relative risk (RR) with 95% CI. In the sibling analysis, we compared exposure among ASD cases to that of non-ASD siblings born to the same mother. We calculated ORs and 95% CIs for women with treated and untreated depression, compared to unexposed. RESULTS We identified 2,154 offspring with ASD among 194,494 mother-baby pairs. Compared to unexposed, the RR of ASD was 1.72 (95% CI 1.54-1.93) for treated depression and 1.50 (95% CI 1.28-1.75) for untreated depression, while the RR was not elevated in women who received antidepressants for other indications (RR =0.73, 95% CI 0.41-1.29). Additional analyses to assess the effects of severity of depression suggest that the risk of ASD in offspring increases with increasing severity, not with the antidepressant treatment. The results of the sibling analysis were similar to the main analysis. CONCLUSIONS Women with depression during pregnancy have an increased risk of having a child with ASD, regardless of antidepressant use.