Treatment specificity is a key principle of aphasia rehabilitation. Auditory-phonological processing impairment is statistically linked to the auditory comprehension impairment in Wernicke’s aphasia (WA). However, a statistical link between comprehension and semantic processing has not been documented, despite an observable semantic impairment in this population. This study explored the relationship between semantic processing and comprehension in WA and how auditory-phonological and semantic processing interact to influence comprehension. New and existing data were collated to produce a group of 39 WA participants. Data was available from multiple neuropsychological assessments in the auditory comprehension, auditory-phonological processing and semantic processing domains. Correlation analyses showed that all these domains were statistically interrelated. Linear regression analyses including an interaction term between auditory-phonological and semantic processing produced a statistically significant model. This model demonstrated that semantic processing had a greater impact on comprehension when auditory-phonological impairments were milder. This result remained significant with the inclusion of age, time post onset, hearing loss and lesion volume as covariates. We interpret that semantic processes have limited impact on comprehension when auditory-phonological processing is severe due to limited access into the semantic system, resulting in low-quality semantic activity which also limits the ability of top-down processing to improve the resolution of the auditory signal. When auditory-phonological processing is less severely impaired, these top-down processes are better able to refine the input signal and support comprehension. Therapy should target auditory-phonological processing in more severe cases whereas a combination of phonological-semantic therapy is appropriate for more moderate cases of WA.