The oral-gut axis may be a route linking periodontal and systemic diseases. Probiotics could be an alternative for the treatment of microbial dysbiotic conditions, including periodontitis. This randomized placebo-controlled clinical trial evaluated the short-term efficacy of systemic probiotics adjunctive to subgingival instrumentation (SI) in promoting a better restoration of the oral-gut microbiotas and greater periodontal clinical outcome. Systemically healthy adults with untreated periodontitis were recruited from a Dental School setting and allocated to receive SI plus placebo (n=24) or probiotics (n=24), one capsule/day for 30 days. Subgingival biofilm and stool were obtained at baseline and 2-months post-therapy for microbiological analyses by checkerboard and 16S rRNA gene sequencing. Differences in all parameters between placebo (n=23) and probiotics (n=19) groups were assessed by non-parametric tests. Most subgingival species and α-diversity decreased after therapies (P<0.05), whereas gut composition/diversity were slightly or not affected by treatments. In parallel, significant clinical improvement (P<0.05) was similar between groups, although a trend for a higher proportion of poor responders in the placebo (60.8%) than the probiotic group (31.5%) was observed (P=0.07). Strong correlations between oral and fecal species were found (P<0.01), and distinct species related to poor response for different therapies (P<0.05). Patients were classified into five periodontitis oral-gut microbial clusters, which correlated differently with attachment loss after therapies (P<0.05). Systemic probiotics combined with SI did not provide short-term additional clinical or microbiological benefits in the treatment of periodontitis; however, response to therapies seemed to correlate with distinct oral-gut microbial profiles.