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Key Points: Question: What drug characteristics are associated with larger proportions of promotional spending allocated to direct-to-consumer advertising? Findings: In this exploratory cross-sectional study of 150 prescription drugs with the highest US sales in 2020, a higher proportion of promotional spending allocated to direct-to-consumer advertising was associated with drugs rated as having lower added clinical benefit than for those having higher added clinical benefit (absolute 14.3% increase in proportion) and with total drug sales (absolute 1.5% increase in proportion for every 10% increase in sales). Meaning: Lower added clinical benefit ratings and higher total drug sales were associated with higher spending on direct-to-consumer advertising as the share of the total; further research is needed to understand the implications of these findings. Importance: Some drugs are heavily marketed through direct-to-consumer advertising. Objective: To identify drug characteristics associated with a greater share of promotional spending on advertising directly to consumers. Design, Setting, and Participants: Exploratory cross-sectional analysis of drug characteristics and promotional spending for the 150 top-selling branded prescription drugs in the US in 2020 as identified from IQVIA National Sales Perspectives data. Promotional spending data were provided by IQVIA ChannelDynamics. Exposures: Drug characteristics (total 2020 sales; total 2020 promotional spending; clinical benefit ratings; number of indications, off-label use; molecule type; nature of condition treated; administration type; generic availability; US Food and Drug Administration [FDA] approval year, World Health Organization anatomical therapeutic chemical classification; Medicare annual mean spending per beneficiary; percent sales attributable to the drug; market size; market competitiveness) assessed from health technology assessment agencies (France's Haute Autorité de Santé and Canada's Patented Medicine Prices Review Board) and drug data sources (Drugs@FDA, the FDA Purple Book, Lexicomp, Merative Marketscan Research Databases, and Medicare Spending by Drug data). Main Outcomes and Measures: Proportion of total promotional spending allocated to direct-to-consumer-advertising for each drug. Results: The 2020 median proportion of promotional spending allocated to direct-to-consumer advertising was 13.5% (IQR, 1.96%-36.6%); median promotional spending, $20.9 million (IQR, $2.72-$131 million); and median total sales, $1.51 billion (IQR, $0.97-$2.26 billion). Of the 150 best-selling drugs, 16 were missing data and key covariates; therefore, the primary study sample comprised 134 drugs. After adjustment for multiple drug characteristics, the mean proportion of total promotional spending allocated to direct-to-consumer advertising for the remaining 134 drugs was an absolute 14.3% (95% CI, 1.43%-27.2%; P =.03) higher for those with low added clinical benefit than for those with high added clinical benefit and an absolute 1.5% (95% CI, 0.44%-2.56%; P =.005) higher for each 10% increase in total sales. Conclusions and Relevance: Among top-selling US drugs in 2020, a rating of lower added benefit and higher total drug sales were associated with a higher proportion of manufacturer total promotional spending allocated to direct-to-consumer advertising. Further research is needed to understand the implications of these findings. This pharmacoeconomic study estimates associations between drug characteristics and the proportion of manufacturer promotional spending allocated to direct-to-consumer advertising. [ABSTRACT FROM AUTHOR]