Pena Nieto's nearly three years in office have been marked by a remarkable number of arrests of the country's most notorious drug kingpins.
The captures of Sinaloa cartel boss Guzman and the chiefs of the Zetas, Knights Templar and Gulf criminal groups earned praise from the United States.
But Guzman's second prison break in 14 years has undermined these achievements, while reviving accusations of corruption and impunity that have shadowed the government's efforts.
"In the best case, this escape is embarrassing," said Alejandro Hope, a former Mexican intelligence agency official.
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"It dents the image of effectiveness that (the government) had projected and it forces a rethink of that narrative that we are doing well in terms of security," said Hope, editor of the security analysis website ElDailyPost.Com.
Following Guzman's arrest in February 2014, Pena Nieto himself had acknowledged in an interview with the US channel Univision that it would be "truly unforgivable" if he escaped from prison again.
Prosecutors interrogated some 30 officials from the Altiplano prison in central Mexico State.
Guzman and his Sinaloa cartel have given headaches to the last three Mexican presidents.
It was during president Vicente Fox's 2000-2006 tenure that Guzman escaped by hiding a laundry cart in a maximum-security prison in western Jalisco state in 2001.
His successor, fellow conservative Felipe Calderon, is notorious for launching the militarized battle against cartels in 2006, which led to an escalation of the drug war that has killed tens of thousands of people.
With Guzman's capture, Pena Nieto signaled that his administration would go after the top leaders of the country's criminal groups.