A retrospective data analysis using 2000–2008 three state Medicaid Analytic eXtract was conducted to examine the prevalence and association of comorbidities (psychiatric and non-psychiatric) with healthcare utilization and expenditures of fee-for-service enrolled adults (22–64 years) with and without autism spectrum disorders (International Classification of Diseases, Ninth Revision–clinical modification code: 299.xx). Autism spectrum disorder cases were 1:3 matched to no autism spectrum disorder controls by age, gender, and race using propensity scores. Study outcomes were all-cause healthcare utilization (outpatient office visits, inpatient hospitalizations, emergency room, and prescription drug use) and associated healthcare expenditures. Bivariate analyses (chi-square tests and t-tests), multinomial logistic regressions (healthcare utilization), and generalized linear models with gamma distribution (expenditures) were used. Adults with autism spectrum disorders (n = 1772) had significantly higher rates of psychiatric comorbidity (81%), epilepsy (22%), infections (22%), skin disorders (21%), and hearing impairments (18%). Adults with autism spectrum disorders had higher mean annual outpatient office visits (32_ASD vs 8_noASD) and prescription drug use claims (51_ASD vs 24_noASD) as well as higher mean annual outpatient office visits (US$4375_ASD vs US$824_noASD), emergency room (US$15,929_ASD vs US$2598_noASD), prescription drug use (US$6067_ASD vs US$3144_noASD), and total expenditures (US$13,700_ASD vs US$8560_noASD). The presence of a psychiatric and a non-psychiatric comorbidity among adults with autism spectrum disorders increased the annual total expenditures by US$4952 and US$5084, respectively.