Autism Diagnostic Observation Schedule-2 is the ‘gold standard’ autism spectrum disorder observational assessment, and it is increasingly used in South Africa. However, its use is limited to English speakers, as it has not been translated into the country’s other 10 official languages. Moreover, the cultural appropriateness of this tool has not been explored in South Africa. The Autism Diagnostic Observation Schedule-2 was translated into Afrikaans and assessed for cultural appropriateness to the ‘coloured’ population from low-middle socioeconomic status backgrounds in the Western Cape Province. Using a mixed-methods approach, three components associated with method bias in the Autism Diagnostic Observation Schedule-2 were investigated: language used, social interactions and activities, and materials. An ethnographic investigation of play, social interaction and social activities was conducted in a community sample (n = 40), and the Afrikaans Autism Diagnostic Observation Schedule-2 was pre-piloted in a clinical sample (n = 7). Results highlighted unique aspects of the language (‘Kaaps’) that need to be considered during Autism Diagnostic Observation Schedule-2 administration. The social interaction demands of the Autism Diagnostic Observation Schedule-2 appeared appropriate, and sufficient familiarity with Autism Diagnostic Observation Schedule-2 materials and activities was found to support the use of the Autism Diagnostic Observation Schedule-2. Guidelines for administration of the Autism Diagnostic Observation Schedule-2 to this population were generated to improve cultural sensitivity and cultural appropriateness and to reduce method bias.