Background: By international standards, water supplies in Perth, Western Australia, contain high trihalomethane (THM) levels, particularly the brominated forms. Geographic variability in these levels provided an opportunity to examine cross-city spatial relationships between THM exposure and rates of birth defects (BDs). Objectives: Our goal was to examine BD rates by exposure to THMs with a highly brominated fraction in metropolitan locations in Perth, Western Australia. Methods: We collected water samples from 47 separate locations and analyzed them for total and individual THM concentrations (micrograms per liter), including separation into brominated forms. We classified collection areas by total THM (TTHM) concentration: low (<60 μg/L), medium (> 60 to <130 μg/L), and high (≥ 130 μg/L). We also obtained deidentified registry-based data on total births and BDs (2000–2004 inclusive) from post codes corresponding to water sample collection sites and used binomial logistic regression to compare the frequency of BDs aggregately and separately for the TTHM exposure groups, adjusting for maternal age and socioeconomic status. Results: Total THMs ranged from 36 to 190 μg/L. A high proportion of the THMs were brominated (on average, 92%). Women living in high-TTHM areas showed an increased risk of any BD [odds ratio (OR) = 1.22; 95% confidence interval (CI), 1.01–1.48] and for the major category of any cardiovascular BD (OR = 1.62; 95% CI, 1.04–2.51), compared with women living in low-TTHM areas. Conclusions: Brominated forms constituted the significant fraction of THMs in all areas. Small but statistically significant increases in risks of BDs were associated with residence in areas with high THMs.