Pro-independence Catalan leaders want Catalonia's regional election on September 27th to serve as a de facto vote on independence and polls show they could win a majority of seats in the wealthy northeastern region's 135-seat assembly.
Investors pulled €21.7 billion ($24.2 billion) in assets out of Spain in June 2015, compared to €1.3 billion during the same time last year, according to Bank of Spain figures.
The risk premium, the extra return investors demand to buy Spanish 10-year government bonds over comparable safe-haven German debt, meanwhile has risen this year to 146 basis points, surpassing Italy's 122 basis points.
Economy Minister Luis de Guindos rejected suggestions that markets had been affected by the independence drive in Catalonia, which is home to 7.5 million people and accounts for a fifth of Spain's economic output.
"I deal a lot with international markets, investors, ratings agencies and the first consideration I want to make is that the topic of a potential independence for Catalonia is neither a rational nor a feasible scenario," he told a business forum in Madrid.
Investors do not "incorporate into their expectations" the possibility of an independent Catalonia, he added.
"It is not a factor that is taken into account by the markets, by capital groups," he added.
Budget Minister Cristobal Montoro echoed his views, saying during an interview with radio Cadena Cope that "nobody believes that Catalonia will be independent".
"Independence is not economically sustainable, it would generate a social crisis. Not only for Catalonia, it would be terrible for the rest of Spain," he added.
"So far the political uncertainty has not reached the point that it interrupts Spain's financing. Now, it is obvious that if anything threatens the economic recovery it is politics in this country," he added.
Spain emerged in 2013 from five years of on-off recession and the government forecasts the economy will grow by 3.3 percent this year - more than twice the average forecast for eurozone countries.