The retention of removable dentures by mini-implants is a relatively recent treatment modality and may lead to minimal post-operative trauma. This study compared post-operative pain and discomfort following the insertion of mini-implants (two or four) or two standard-size implants for the retention of mandibular overdentures. One hundred and twenty edentulous participants (mean age 59.5 ± 8.5 years) were randomly allocated into three groups according to received treatment: (GI) four mini-implants, (GII) two mini-implants or (GIII) two standard implants. Seven days after implant insertion, patients answered questions (100-mm VAS) relating to pain, swelling, and discomfort with chewing, speech and hygiene, considering their experiences during the 1st and 6th day. Groups were compared by two-way anova (α = 0.05). All participants (GI: 38; GII: 42; GIII: 40) were analysed after 7 days. At the 6th day, GI felt significantly higher pain than GII and GIII. GI also reported more difficulty in performing oral hygiene practices than GIII during the 1st day. There was no significant difference between groups for the other questions and periods. No participant suffered unexpected side effects. The use of four mini-implants induces more intense post-operative pain at the 6th day than the insertion of two mini- or conventional fixtures, as well as more difficult oral hygiene on the 1st day. Clinicaltrials.gov, NCT01411683; FAPESP, 2011/00688-7 and 2011/23347-0.