Importance: Tolerability is a key determinant of the effectiveness of epilepsy treatment. It is important to evaluate whether the overall tolerability has improved. Objective: To identify factors associated with poor tolerability of antiseizure medications (ASMs) and examine temporal changes in tolerability. Design, Setting, and Participants: This was a longitudinal cohort study at a specialist clinic in Glasgow, Scotland. Patients with newly diagnosed and treated epilepsy between July 1982 and October 2012 were included from 2282 eligible individuals. They were followed up until April 2016 or death. Data analysis was completed in August 2019. Exposures: Antiseizure medications. Main Outcomes and Measures: Univariable and multivariable survival analyses were performed to examine associations between potential risk factors and development of intolerable adverse effects (AEs). Intolerable AE rates of the ASMs as the initial monotherapy were compared between 3 epochs (July 1982-June 1992, July 1992-June 2002, and July 2002-April 2016). Results: Of 1795 patients, 969 (54.0%) were male, and the median (interquartile range) age was 33 (21-50) years. A total of 3241 ASMs were prescribed during the period, of which 504 (15.6%) were discontinued within 6 months owing to intolerable AEs. Children younger than 18 years had lower intolerable AE rates than adults (vs aged 18-64 years: Adjusted hazard ratio [aHR], 1.58; 95% CI, 1.07-2.32; vs aged ≥65 years: AHR, 1.90; 95% CI, 1.19-3.02) while female individuals (aHR, 1.60; 95% CI, 1.30-1.96) and those who had more than 5 pretreatment seizures (aHR, 1.24; 95% CI, 1.03-1.49) were associated with having higher risk. For each ASM trial, the risk of intolerable AEs increased with the number of previous drug withdrawals due to AEs (aHR, 1.18; 95% CI, 1.09-1.28) and the number of concomitant ASMs (aHR, 1.31; 95% CI, 1.04-1.64). The proportion of second-generation ASMs prescribed as the initial monotherapy increased from 22.3% (33 of 148) in the first epoch to 68.7% (645 of 939) in the last (P <.001). Although differences in intolerable AE rates and types of AEs were found between the ASMs, there was no difference in the overall intolerable AEs rates to the initial monotherapy across the 3 epochs (first: 10.1% [15 of 148]; second: 13.8% [98 of 708]; third: 14.0% [131 of 939]; P =.41). Conclusions and Relevance: In this cohort study, the increased use of the second-generation ASMs had not improved overall treatment tolerability. Greater effort to improve tolerability in ASM development is needed..