The S&P 500 has closed lower while the Nasdaq reached a record high as investors balanced worries about the slowing pace of economic recovery with expectations that the Federal Reserve will maintain its accommodative monetary policy.
Amgen Inc and Merck & Co fell after Morgan Stanley cut its rating on the stocks to "equal-weight" from "overweight".
The Nasdaq was supported for most of the day by Big Tech stocks that have fuelled Wall Street's gains in recent years.
Apple and Netflix both hit record highs.
"You could call it a gravitation toward Big Tech. As people feel a bit uncertain about how COVID will play out, you don't have your reopening worries with those companies," said Tom Martin, senior portfolio manager at Globalt Investments in Atlanta.
Much of the rest of Wall Street fell.
Most of the eleven sub-indexes traded lower, with economy-sensitive sectors like industrials, real estate and materials among the deepest declines.
Tepid August payrolls data on Friday last week raised concerns that the economic recovery was slowing down.
On Tuesday, Morgan Stanley cut its rating on US stocks to underweight, pointing to risks related to economic growth, policy and legislation and warning it expects the next two months to be "bumpy".
Accommodative central bank policies and reopening optimism have pushed the S&P 500 and Nasdaq to record highs over the past few weeks but concerns are growing about rising coronavirus infections due to the Delta variant and its impact on the economic recovery.
Analysts on average expect S&P 500 companies to increase their earnings per share by 30 per cent in the September quarter following a 96 per cent surge in the second quarter, according to I/B/E/S data from Refinitiv.
The Dow Jones Industrial Average fell 0.75 per cent to end at 35,104.56 points, the S&P 500 lost 0.33 per cent to 4,520.26 and the Nasdaq Composite climbed 0.07 per cent to 15,374.08.
The S&P 500 remains up about 20 per cent year to date and the Nasdaq is up about 19 per cent.
Boeing Co dropped after Ireland's Ryanair said it had ended talks with the plane maker over a purchase of 737 MAX 10 jets worth tens of billions of US dollars due to differences over price.
Match Group Inc shares jumped after the S&P Dow Jones Indices said on Friday the Tinder parent will join the benchmark index.
Columbia Property Trust Inc surged after Pacific Investment Management Company said it would buy the company for $US2.2 billion ($A3.0 billion).