BackgroundThe Population Assessment of Tobacco and Health (PATH) provides annual prevalence data on youth use of electronic nicotine delivery systems (ENDS). However, trends may be complicated by COVID-related changes in survey mode (self-completed vs. telephone interview) across 2019–2021. MethodsTrends in past 30-day (P30D) ENDS use over PATH waves 5 (2019; 100 % self-completed), 5.5 (2020; 100 % telephone interview), and 6 (2021; 33.5 % self-completed, 66.5 % telephone interview) were examined among continuing youth, overall and within survey mode. Further analyses examined the nature of these changes by examining 1) potential response biases in social contexts of nicotine use, and 2) sources of ENDS over time. ResultsTelephone interviewees were less likely to report ENDS use (4.6 % vs. 8.6 % for self-completers), and more likely to report social disapproval of nicotine use, suggesting a reporting bias in telephone interviews. Survey-mode-naïve analyses suggested a large decline in P30D ENDS use prevalence between 2019–20 (10.2–4.6 %) followed by an apparent uptick in 2021 (5.9 %); however, comparing like-to-like survey modes showed a more modest decline (10.2 % in 2019; 8.6 % in 2021; self-completed) with no change between 2020 and 2021 (4.6 % in both; telephone interviews). Analyses suggested that the mode effects were partly, but not wholly, related to social desirability effects. DiscussionChanges in PATH survey mode introduced artifacts into ENDS use prevalence, possibly due in part to social desirability bias suppressing reporting in telephone interviews, rather than a true uptick. It is essential to account for survey mode in PATH surveys.