It is expected to retain power after the long-time opposition movement Renamo divided, with members breaking away to form the Democratic Movement of Mozambique (MDM) in March.
Guebuza was among the first to cast his ballot in the capital, Maputo.
He said he was confident his party and "candidate will win".
It is the fourth time the southern African country has held national elections since the introduction of multi-party democracy in 1994.
'Force of Change'
Guebuza, who is running on a "Force of Change" ticket, faces two challengers - Afonso Dhlakama, who heads Renamo, and Davis Simango, the MDM leader.
Dhlakama, who led a 16-year armed struggle against Frelimo, is also trying to court foreign investment that helped the economy, heavily dependent on agriculture, grow more than six per cent last year.
Expansion is forecast at 4.5 per cent for 2009.
Analysts expect Guebuza and his Frelimo to win a majority but not the two-thirds that would allow the party to change the constitution.
Gil Laureciano, a political analyst, said: "It's quite clear that he will win, but I don't expect him to get an absolute majority in parliament because most of the voters were neither born during the liberation struggle nor the devastating 16-year war against Renamo.
"They don't care about what happened in the past, so they will be voting for better job opportunities, for quality education and housing."