Up to 70% of individuals with schizophrenia experience inadequate response to antipsychotic treatment potentially due to insufficient exposure due to nonadherence or to medication ineffectiveness. Measurement of adherence is necessary to ensure correct interpretation of trial results. Patient self-report and clinician opinion of nonadherence, while common, are unreliable, and few completed trials offer guidance on determining inadequate response at screening/baseline. We present trial design and adherence results from ENHANCE (NCT02970292), a phase 3 study that assessed adjunctive therapy of pimavanserin, a selective serotonin 5HT2A inverse agonist/antagonist, in patients with schizophrenia and inadequate response to their current antipsychotic. At ENHANCE screening, a blood sample from patients with documented treatment stability (≥8 weeks pre-screening) was tested for the presence or absence of the main antipsychotic. Postrandomization sampling and assessment of the main antipsychotic and pimavanserin occurred at baseline, and weeks 1, 3, and 6. A total of 598 blood samples from 668 patients were tested at screening (including 35 re-screens). Measurable levels of the main antipsychotic were detected in 90.6% of screened samples. At ENHANCE baseline, 94.9% of patients were considered adherent to their main antipsychotic, with adherence maintained at weeks 1, 3, and 6. High adherence was also found for adjunctive pimavanserin. In 198 patients randomized to receive pimavanserin, measurable levels of pimavanserin were detected in 185 of 188 (98.4%) at week 1 and 178 of 180 (98.9%) at week 3. Adherence to pimavanserin was demonstrated for 96.8% of those patients who completed 6 weeks of treatment or who terminated early.