Instead of British scientists leading the way with new breakthroughs, it might be better to focus instead on taking, developing and exploiting the discoveries of others.
Britain has a proud history of "firsts" in science and engineering, from the invention of the steam engine to penicillin and cracking the structure of DNA.
But Mr Willetts said "being first" was not an argument that was likely to persuade hard-headed Treasury officials.
Speaking at the Royal Institution in London – which during its 200-year history has been closely associated with pioneering scientists such as Michael Faraday, inventor of the electric motor – he said: "Consider the spur of national pride – the pride, so to speak, of planting our flag on Everest first.
"There are, of course, individuals – whether Olympic medallists or Nobel prize winners – whose achievements can be regarded as a vivid reflection of the health of the country that produced them.
"We all take pride in them. But none of this is an economic argument for being the first person to make a scientific discovery.
"Why does it matter economically that we should be first or that something should be discovered by a Brit?
"We need enough good science so we have the capacity to tackle a new problem, to react effectively to scientific breakthroughs however or wherever they may arise, and to capitalise on those breakthroughs via research programmes and business initiatives of our own."
Mr Willetts stressed he was not saying Britain should entirely give up being first. But in a tough economic climate, it was necessary to take an economic approach.