Introduction: The association between increasing diagnosis rates of autism-related disorders (ASD-R) in Swedish regions and diagnosis rates of major depressive disorders (MDD) in adolescents remains unexplored. Methods: Following STROBE guidelines, this pre-registered (https://osf.io/duvq7) observational study, utilizing registry data from 2008 to 2022 across the 21 Swedish regions, employed a generalized linear mixed model (GLMM) to analyze the association between ASD-R (ICD-10: F84) and MDD diagnosis rates (ICD-10: F32) in 15-19 year olds, with registered primary diagnoses considered. The GLMM included psychiatric care affiliation rates (PCAR) as fixed effects and variations across years and regions as random intercepts. The model incorporated bipolar disorder (BD) rates and the male-to-female ratio of ASD-R diagnoses when justified. Separate models were created for combined sexes, males, and females. Results: A significant inverse relationship was observed between ASD-R and MDD diagnosis rates across all sex groups. In the combined-sex model, the mean ratio was 0.40 (P = 0.003), while the sex-specific models showed ratios of 0.28 for males (P < 0.001) and 0.37 for females (P = 0.017). All ratios were significantly below 1, indicating a negative association between ASD-R and MDD diagnosis rates. Conclusions: The study's observational nature limits causal inferences, but findings reveal that higher primary diagnosis rates of ASD-R correlate with lower primary diagnosis rates of MDD in adolescents of both sexes, although more pronounced in males. These results highlight the importance of further research on the relationship between ASD-R and MDD diagnosis rates, emphasizing the need for prospective, longitudinal, and individualized register data that include both primary and co-diagnoses.