More than half of the Welsh Assembly Government's 10 flagship technium business innovation centres are to close.
They have been criticised for not delivering value for money or creating as many jobs as expected.
The six closing are at Aberystwyth, Baglan, Bangor, Pembroke Dock, Llanelli and in the Sony plant in Bridgend.
The assembly government said it "would not abandon" the existing tenants and would help them find new premises.
Four other techniums at Swansea University, the city's SA1 docklands development, St Asaph and Cwmbran will be retained.
Launched in 2001, the centres were aimed at helping new science and technology businesses to develop.
However, they cost hundreds of millions of pounds to build and run, and an assembly government internal audit for 2008 raised questions about financial controls within the programme.
The closure announcement is not directly linked to the Welsh draft budget published on Wednesday but the assembly government said closing the six centres would save a substantial amount of money.
Deputy Minister for Science, Innovation and Skills Lesley Griffiths said: "This year we announced a whole new approach to economic development.
"It outlined our vision of creating the best conditions to enable the private sector to grow and create jobs.
"The world has changed so the way we provide business support has to change - our investment needs to be smarter.
"We are focusing on supporting economic growth and the techniums we are retaining will be part of this approach.
"They will continue to provide incubation support for new, growing companies.
"We will be looking at the options for those techniums we are not keeping in the network.
"Whatever the outcome, let me reassure current tenants that we will not abandon them and will fulfil our obligations by finding alternative office space if required.
"This will be a gradual process and we will not see techniums closing overnight."
AM Andrew Davies, who was economic development minister between 2002 and 2007, said he was very disappointed but not surprised.
He told BBC Radio Wales: "It's been a long time coming. I don't blame ministers for this, I hold responsible senior management and senior civil servants in the Department of Economic Development and Transport responsible for the effective waste of £100m of public expenditure."
"The weaknesses of the technium concept have been identified over many years. Audit reports on it have said it is very good in principle but delivery is poor.
"There was no strategy for the roll out of technium and it was flawed in terms of its day-to-day management.
"The original concept that you would get high growth potential, hi-tech companies in there developing in their early years and then move on hasn't happened.
"As economic development minister, and susequently finance minister, I asked over and over again for data on performance and I was fobbed off by senior officials."
People should have been appointed to run the centres who knew the business world and who would have got the right companies in them, Mr Davies said.
He is to write to the chair of the public accounts committee asking for an investigation into how the techniums were run.
A spokesman for the permanent secretary at the assembly government said: "Andrew Davies has expressed his personal views on a number of occasions recently.
"We are focused on supporting ministers during this particularly busy and challenging period and have no wish to comment on anecdotes."