Importance Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses. Objective To determine whether seizure frequency in FTRE improves over time. Design, Setting, and Participants The Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample. Exposures Participants were treated with multiple interventions at their physicians’ discretion. Main Outcomes and Measures The primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes. Results Of 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P &lt; .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices. Conclusions and Relevance Findings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretation of open-label studies positing disease-modifying effects and further research into FTRE treatment response.